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University of Texas, Austin Project Title: Small molecule inhibitors of the desuccinylation process may be a novel way to treat cancer. HBO has said they are still committed to Simmons and is excited to work with him on future programming. While Eli Manning's future as a player with the NY Giants is uncertain after being benched by the team earlier this week, the possibility of a broadcasting career might be on the horizon. Brian Billick will not be returning to Fox Sports after the network decided not to offer the NFL analyst an extension to his expiring contract.
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Signs and symptoms of low blood sugar may include: Yeast infection of the penis balanitis or balanoposthitis. Talk to your doctor about what to do if you get symptoms of a yeast infection of the vagina or penis.
Talk to your doctor about factors that may increase your risk of bone fracture. Low vitamin B 12 vitamin B 12 deficiency. Using metformin for long periods of time may cause a decrease in the amount of vitamin B 12 in your blood. Your doctor may do blood tests to check your levels. Tell your doctor if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. This site is published by Janssen Pharmaceuticals, Inc.
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This information is intended for the use of patients and caregivers in the United States and Puerto Rico only. Laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. Skip to main content. Exclusive tools and information to help you set and keep track of weekly healthy goals. Exercise Safely in Winter Weather. Five Workout Motivational Tips. How to Hydrate for Your Active Life.
Easy Exercises to Do Around the House. Walking Your Way to Better Health. Simple Healthy 5-Ingredient Dinner Recipes. Use of anesthetic drugs by non-anesthesiologists in intensive care units and outpatient settings continues to grow. At the same time, anesthesia-related morbidity, including intra-operative awareness, altered neurological development and delirium in children and cognitive dysfunction in the elderly remain significant problems.
Despite the central role of anesthesiology in modern healthcare, research in this field is overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with no attention to developing new approaches.
We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral- physiological state through precisely timed control of specific brain circuits. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: Each year approximately three quarters of a million Americans will have a new myocardial infarction MI , and approximately half a million will have a recurrent MI.
No current therapies exist that directly address the negative left ventricular remodeling process that occurs post-MI and results in heart failure. There is therefore a strong clinical need to develop novel therapies to treat MI.
This research program will establish a new paradigm in the design of treatments for healing heart tissue post-MI. Specifically our plan is to develop self-assembling materials programmed to form a healing scaffold in damaged heart tissue immediately following MI. In the proposed, unprecedented approach, the materials will be designed to be injected intravenously rather than directly into heart tissue, and will target and self-assemble in the MI, providing a scaffold to recruit endogenous cells for cardiac repair.
This research proposes to change the current approach to understanding the molecular basis of memory. Our approach challenges the current focus on quantitative identification of synaptic RNAs by developing new technologies to address protein synthesis-dependent synaptic plasticity: These will allow us to redefine the problem from two new superimposed perspectives: Specific synapses will be studied: These complexes will be compared with a delineation of all ribosome-mRNA synaptic complexes present in the same dendrites, allowing us to validate interactions by identifying translationally regulated synaptic mRNAs synaptic translational profiling.
Regulated dendritic RNAs will be further validated by assessing for their translational state in well-studied paradigms of protein synthesis-dependent synaptic plasticity. Psychiatric disease represents the leading cause of disability both in the U. In general, achieving high-resolution information on any biological system typically comes at the expense of the global perspective that is often essential to understanding.
This research project will directly address this challenge, in part by developing and applying new chemical engineering-based technologies to rapidly transform intact, impermeable and opaque biological tissue into macromolecule-permeable for labeling and interfacing and transparent form.
The CLARITY technology will be developed with compatible readout methods for extracting volumetric activity and tissue history, information which can then be linked to global wiring and local molecular phenotypes obtained from the very same tissue or organism.
The approach will be developed in the vertebrate central nervous system, challenging for its low accessibility and high complexity, but CLARITY is applicable to any biological system including to the human brain and to models of neurological and psychiatric disease.
Recently, an elegant technique was developed allowing for unprecedented control and specificity in mapping the molecular and cellular properties of neural circuits. Some of the most burning questions in the neurobiology of pain, affect and addiction lend themselves particularly well to the implementation of optogenetic neural modulation techniques, yet these still require drastic miniaturization of circuits, power and light sources for full implementation in diverse neuroscience applications.
Enhancer Therapy Grant ID: Current efforts are to determine the biochemical and biological roles of sequence- specific transcription factors and their associated co-regulators at gene-specific and genome-wide scales.
This research project will use a combination of biochemical, cellular and genetic model systems are used, incorporating macrophage-specific knockouts, microarray technologies, massively parallel sequencing and bioinformatics approaches, to unravel the contributions of specific factors to the development of specialized macrophage functions in immunity and the pathogenesis of inflammatory diseases. One of the primary focus areas of our research is working to integrate physiologically relevant sensory feedback with prosthetic limbs.
To this end we employ a variety of approaches that interweave disciplines such as electrophysiology, psychophysics, biomedical engineering and cognition. Our research team is composed of an interconnected and communicative network of clinicians, engineers, and scientists. This helps us to provide pathways from basic science discoveries that can be used to address clinical needs with transition directly to patient care.
Pulmonary infections by microorganisms, such as Mycobacterium tuberculosis and Pseudomonas aeruginosa, are annually responsible for the morbidity and mortality of millions of immunocompromised individuals worldwide. Despite the availability of drugs that successfully eradicate these pathogens in vitro , they are far less successful in vivo.
Due to the challenges of working in situ , most studies of infectious disease agents IDA are conventionally performed with representative isolates and imperfect disease models in the laboratory; by necessity, they are highly reductionist.
Very few direct measurements of the physiological state of drug-tolerant populations in the host exist, and little is known about which metabolic pathways are actually at play, much less how they change over time in response to co-evolving conditions within the lung.
We will tackle this critical knowledge gap using an approach inspired by geobiology. Geobiologists are experienced in studying the growth and metabolism of microbial populations in poorly accessible natural habitats by combining molecular biology and stable isotope geochemistry. We propose to study IDA within infected lungs using these tools, with the goal of defining the composition, growth rate and metabolism of the microbial community at different stages in disease progression with high spatial resolution.
The onset of distant metastasis marks the stage of cancer progression where the disease is no longer considered curable. Currently, clinicians are unable to determine when metastases have occurred until the cells have colonized one or more distal sites and often affected the function of the effected organ.
We propose an early detection system based on developing an implant that would recruit metastatic cancer cells and a sensor to identify when these cells have colonized the implant. Recruiting the metastatic cancer cells would initially function to reduce the burden of circulating tumor cells and limit their colonization in other tissues.
Investigating the design of implants that recruit metastatic cancer cells is expected to further define the biology of the pre-metastatic niche. Taken together, the development of an implant to recruit metastatic cells and a non-invasive technology to monitor growth could transform current clinical approaches to cancer treatment.
With nearly 15 million units of red blood cells RBCs transfused to about 5 million patients in the U. During hypothermic storage, a significant fraction of stored RBCs becomes irreparably damaged and the storage medium accumulates known mediators of toxicity as byproducts of RBC metabolism and degradation. The goal of this project is to develop technology for high-throughput removal of irreparably damaged cells and toxic mediators accumulating in the storage medium from RBC units during the transfusion process.
In this project, we will systematically explore the design of smart nanobjects able to transduce molecular level sensing of indicators of health status a.
Our results will lay groundwork for broadly applicable families of theranostic providing therapy upon diagnostics devices that would be able to autonomously monitor and correct disease states.
All mRNA molecules are subject to posttranscriptional gene regulation PTGR by hundreds of RNA-binding proteins RBPs involving sequence-dependent modulation of splicing, cleavage and polyadenylation, editing, transport, stability, and translation. The major goal of this application is to identify and characterize the interaction network of mRNA-binding transport and shuttling proteins at the sequence, structural, and functional level and to establish theoretical and experimental models that relate these features to RNA transport processes and PTGR.
Our approach involves deep sequencing methodologies suitable for broadly mapping interaction sites between RBPs and their RNA targets in human cells, followed by integrated annotation of binding sites on transcripts across libraries via a probabilistic graphical modeling approach to identify prevalent states reflecting particular site configurations.
As computed interaction models emerge, these will be studied by biophysical and structural methods using natural, as well as designed RNA recognition element representing RNA ligands together with their respective recombinant proteins. We anticipate the identification of numerous important regulatory regions in mRNAs, as well as uncover mRNAs and RBPs particularly vulnerable to mutation and deregulation in disease states.
The role of the innate immune system in aging and AD has received limited study and is poorly understood. This is due in part to confusion regarding microglial cells and how they relate to the peripheral innate immune system. This advance presents a unique opportunity to determine the functions and dysfunctions of innate immune cells in brain aging and the development of AD.
We will study the innate immune system both in animal models and aging human subjects and in human postmortem tissue. The existing health care system requires an individual to visit a health care facility to conduct point-in-time tests to monitor even the most basic health status markers, which can miss fluctuations in body chemistries that are vital to accurate diagnoses, particularly in high-risk populations.
Continuous multi-chemistry health sensors have the potential to dramatically change health care by paving the way for decentralization of health care delivery and shifting the focus away from reactive treatment to preventative maintenance. We propose to transform current testing paradigms by developing highly miniaturized, injectable, sensors for continuous and simultaneous monitoring of multiple body chemistries.
Sensor molecules that glow somewhat like fireflies when they come in contact with certain biomarkers are embedded into specially engineered tissue-like biomaterials. The sensor molecules are embedded in soft, tissue-like biomaterials that become part of the tissue in which they are injected, and do not cause the typical foreign body rejection response. The sensors are injected under the skin and monitored optically using a miniaturized, wireless, Band-Aid-like reader for continuous measurement or a hand-held wand for periodic self-measurement, depending on the clinical need.
The data may be viewed via cell phone or at a remote location, allowing the individual, physician, or other care providers to access medical data without the need for in-person examination until a critical threshold is met. The research project will develop a systematic in vivo discovery approach for identification of critical genes and pathways that limit the anti-tumor activity of cytotoxic T cells. Our hypothesis is that shRNAs which target critical inhibitors in dysfunctional T cells can reprogram them to undergo substantial expansion in tumors.
T cells will be genetically modified with shRNAs and then transferred into tumor-bearing mice so that enrichment of particular shRNAs within tumors can be quantified. This in vivo approach will also be used to address a second related problem in oncology, the identification of combination therapies that act in a highly synergistic manner on defined cellular pathways.
The therapeutic activity of these human T cells will be tested in a xenotransplant mouse model on human melanomas, as a key step towards translation of our discoveries into the clinic. Figure describes a device that can manipulate small model nematodes worms in fluidic micro-channels. Populations of worms are treated with different drug compounds and then monitored for health of their entire nervous system at ultra-high speeds.
This device will enable the discovery of new drugs to delay or prevent the progression of neurodegenerative diseases and aging. Neural activity is recorded from channels distributed across two microelectrode arrays implanted in the premotor and primary cortex. Data are decoded in real time to control the cursor. Image shows a sirtuin enzyme catalyzing the removal of a protein modification lysine succinylation from metabolic enzymes. This activity is required for the malignant growth of cancer cells.
Small molecule inhibitors of the desuccinylation process may be a novel way to treat cancer. Image shows a schematic of genes being modified from bacteria, and then inserted into human immune cells.
Image shows microscopic circuits that will enable monitoring of the brain's electrical activity using magnetic imaging techniques such as magnetic resonance imaging MRI. Following injection into brains, the microdevices shown in green will convert neuronal voltage signals into tiny magnetic fields shown in dashed blue lines that will be detectable by MRI.
Some of these memory T cells migrate into peripheral tissues, including skin, lung, and gastrointestinal tract, and become resident long-lived memory T cells TRM that protect against infection. Figure illustrates the key components of an innovative and non-pharmacologic treatment for Attention Deficit Hyperactivity Disorder ADHD that combines cognitive and physical exercises.
Part of the figure shows a child sitting at a classroom computer and doing one of the cognitive exercises. A second part of the figure shows a group of children engaged together in a group physical exercise in the gym that requires ball skills, concentration and memory. Last part of the figure shows a brain.
Color-coded reconstruction of three pyramidal neurons in the mouse brain. There are a number of axons making synapses on the beige neuron. Synapses are the sites of communication between neurons. Small, round particles, on the order of 10 microns, can be mixed with stem cells of the same approximate size to form aggregates of the cells and materials.
As stem cells secrete growth factors, the entrapped particles can capture the secreted molecules. The aggregates can then be disrupted in order to retrieve the particles, now loaded with the stem cell-derived factors. The stem cell factor-laden particles can then be injected at different sites of disease or injury in adult mammals in order to promote tissue repair and regeneration. Image displays a high-resolution, high magnification electron micrograph of mitochondria isolated from heart.
For high sensitivity and specificity in tumor detection, this system is equipped with 4 input channels, shown in 4 panels: Image shows a mesenchymal stem cell MSC on the bottom of the figure transferring red-dye labeled pieces of RNA into a target neuronal cell blue arrow.
African trypanosomes are blood-borne parasites that use their surface coat as a decoy to trick the immune system into making long-lasting antibody responses. Image shows trypanosomes surrounded by immune cells B cells.
Trypanosome coats will be modified shown in the middle panel to trick the immune system into making therapeutic antibodies against disease-associated targets inserted epitope, shown in the right panel. Spina bifida is shown on the left, in magnetic resonance imaging MRI , showing the open spine and exposed spinal nerves arrow. This and other Neural tube defects NTDs are due to a complex interaction of genetic predisposition and environmental factors, including the addition of methyl groups to DNA.
A major source of methyl groups is the vitamin, folic acid. Such maps from patients with spina bifida will be compared with healthy controls to determine which genes are under- or over- methylated in affected patients and could contribute to their risk of having an NTD.
Structure of a Membrane Protein in a Lipid Membrane: Direct Conversion of Fibroblasts into Neurons: Microbes that cause disease are becoming resistant to antibiotics faster than we can find new ones, making many common infections untreatable and life threatening.
Innovative approaches are urgently needed to speed up the discovery of new anti-infectives. This project aims to achieve a paradigm shift in antimicrobial drug discovery by finding next generation anti-infectives that prevent disease by blocking pathogen adaptation to host physiology.
Rather than simply preventing bacteria from growing, these new sophisticated drugs will prevent disease by interfering with a microbe's ability to interact with the human body. The findings will help to identify drugs that cure otherwise lethal infections.
A current paradigm in biology is that basal cells present in the epithelial lining of some organs never come into contact with the inner luminal side of the organ. They will take this work one step further and create new model systems to determine the 3-D relationships and functions of different epithelial cell types as the basal cells detect and respond to various drugs, hormones, chemicals and pathogens that appear in the cavity of the organ.
A better understanding of how these novel basal cells communicate with adjacent cells will help define disease mechanisms and suggest new diagnostic and therapeutic strategies for male infertility, and diseases of the lung, including asthma, chronic obstructive pulmonary disease COPD and cystic fibrosis CF.
High-throughput assays are indispensable for comprehensive functional proteome research. To accelerate research in this field, new protein capture tools for the detection and identification of specific proteins are needed. The reagents must be stable to thermal and proteolytic degradation, have high affinity, be easy to produce and present low cross-reactivity.
This proposal presents an innovative approach for screening and selecting a new class of highly stable protein capture reagents and developing a new versatile approach for ligand immobilization that together enable rapid production of cyclotide-based microarrays for proteomics research.
These technologies have the potential to accelerate science discovery and to realize the diagnostic and prognostic benefits of clinical proteomics. Mitochondrial dysfunction has been associated with many diseases, including neurogegeneration, diabetes and cancer, although its exact role in the development of these diseases remains controversial. This proposal tests the paradigm-shifting hypothesis that mitochondrial-derived proteins MPDs play a previously unappreciated role in the regulation of cellular and organismal function, and that disregulation of MDPs is important in disease development.
Understanding the role of MPDs may lead to development of new therapeutic and diagnostic targets. This project aims to develop a revolutionary screening platform that will allow for the rapid isolation of hundreds of high affinity and specificity synthetic ligands for proteins in a highly parallel fashion. The identification of large numbers of protein ligands is a high priority for biomedical research.
Such ligands could be employed as reagents to construct tools for the discovery of diagnostically useful disease biomarkers. They could also serve as drug leads for a variety of therapeutically interesting targets. Because the ligands will be peptoids, which can be easily synthesized in large quantities by research laboratories lacking specialized organic chemistry skills, the ligands will be more widely accessible to the research community than would be most other classes of protein binding-molecules.
The use of RNA interference RNAi based gene silencing holds great promise as a clinical therapy for many diseases, but such applications face many hurdles including reliable methods for delivery to target tissues and organs. The investigators have developed a novel microparticle technology for oral RNAi delivery to macrophages in living animals and demonstrated in vivo gene silencing and amelioration of inflammation.
They now propose to develop this method as a clinical strategy for treating a number of important diseases in which macrophage-mediated inflammation plays a role including type 1 and 2 diabetes, atherosclerosis, arthritis and inflammatory bowel diseases.
Most of our current understanding of signal transduction pathways relies on solution biochemical analyses of protein interactions and on bulk measurement of select pathways averaged over large cell populations. This is a proposal to establish a new paradigm for the study of cellular signal transduction that combines biosensor design and live cell imaging to produce a transformative approach to studying cellular signal transduction and decision processes.
These advances promise a breakthrough in our ability to probe complex, spatially and temporally organized signaling processes in cell models of normal and diseased physiology. A fundamental property of the brain is that our experiences cause modifications in the number and strength of the connections among neurons. These changes, which are thought to underlie memory and cognition, require the precise control of the synthesis of specific proteins at the sites of these connections.
The mechanisms governing this local synthesis of synaptic proteins are poorly understood, although it is known that disruption of this process has severe consequences. This defect is thought to be responsible for Fragile-X syndrome, the most common inherited form of mental retardation. This proposal describes a method that can provide individual reporters of the regulation of protein synthesis for each gene in the genome, and can identify the regulatory mechanisms controlling each one.
The work will be conducted in Drosophila although the high degree of conservation of gene regulatory mechanisms and function, is it likely that much of what we learn will be transferable to humans. The success of artemisinin-based combination therapies in combating Plasmodium falciparum malaria has inspired calls for the eradication of this devastating parasitic disease. However, new reports of emerging artemisinin resistance, and the absence of alternative first-line drugs, highlight an urgent need for new control methods.
Exploiting the dependency of fatty acid synthesis by liver stage parasites, they will develop fatty acid synthesis-deficient, genetically-attenuated parasite vaccines that arrest in the liver, causing a host immune response that protects against infectious challenge. In addition, they will target parasite synthesis as well as salvage of host fatty acids, as a means to develop novel prophylactic and curative medicines that can prevent and control this widespread and devastating disease.
A tremendous gap exists between available culture and animal models and methods that can extract detailed information on cell-cell communication networks governing system responses to perturbations, such as an inflammatory cue. Networks inherently operate in a complex, interlinked fashion, and often exhibit non-intuitive outcomes from intervention at a particular point in the network, as evidenced by failure of many targeted therapeutics to operate in the clinical setting after promising results in currently- available preclinical trials.
The goal of this project is transform our ability to probe cell-cell communication networks in human cell systems via linking systems biology with tissue engineering. Development of new methods that do not rely on genetic manipulation of the cell populations will generate valuable information about systems operation.
A central paradigm of medical genetics is that the phenotype of a deletion syndrome results from the disruption of the deleted genes themselves. In direct contradiction to this dogma is the idea that genetic diseases can be caused or modified by changes in physical, long-range interactions that normally occur between loci that are now deleted and genes that are far from the deleted region when plotted on a linear genetic map.
In some cancers and genetic diseases, long range associations between genes are lost because a part of a chromosome becomes deleted. By examining the network of long range interactions among genes, we will learn how diseases are caused by the change in the expression of many genes which become abnormally regulated when the interactions are lost. This project seeks to address the mechanisms underlying the integrity of tissues, networks of interacting cells and matrices.
The project will determine how cells come together to form tissues, and test the hypothesis that tissue integrity results from the integration of information that arises from the dynamic interactions between the different cell types and the matrices that bind these cells together. Using the filtration barrier of the kidney cortex as a model system, the researchers will apply a combination of mathematical models and engineering approaches to develop a 3-D tissue assembly to study this phenomenon.
These studies will identify general design principles for assembling functional tissues that can aid in understanding disease processes and for screening for new drugs. The detection of proteins is fundamental to essentially all biomedical research.
Current strategies to detect proteins include techniques such as Western blotting and enzyme-linked immunosorbent assays. Currently, there are no techniques that permit the levels of endogenously expressed proteins to be monitored in real time in living cells. The sensors will be used to monitor protein expression in cells in real time. The experiments will result in powerful new tools for protein detection that will markedly enhance and expand biomedical research.
More than 30 million Americans suffer from unrelieved chronic pain, such as nerve injury-induced neuropathic pain. Although a considerable amount is known about how chronic pain is induced, little is known about how acute pain naturally resolves.
Current management of chronic pain mainly focuses on two types of drugs, ones that treat pain symptoms by blocking neurotransmission and those that modify disease progression by suppressing neuroinflammation. This project employs a novel approach for chronic pain therapy using newly uncovered endogenous pro-resolving lipid mediators. The project will investigate whether and how these mediators can prevent and reverse neuropathic pain after nerve injury.
The results from the proposed studies are likely to transform and positively impact on the entire pain community, from acute postoperative pain to chronic inflammatory and neuropathic pain. Protein-capture reagents are indispensable for delineating the molecular mechanisms of diseases, to detect and characterize cellular abnormalities, and to characterize biological effects of drugs.
However, the current paucity of high-quality protein-capture reagents presents a major bottleneck in virtually all areas of biomedical sciences. This project will establish a totally new approach to facile generation of detection reagents that are high performance, easy to produce and easily made available to the research community.
This innovative and powerful technology will fill a major void in the currently available molecular tools and will have a major impact on virtually all areas of molecular biomedical sciences, diagnosis and drug development. The adult human intestine performs essential roles in physiologic homeostasis including digestion, nutrient absorption, secretion of hormones, and immune functions.
Diseases of the intestine, such as inflammatory bowel diseases, infection, malabsorptive states and neoplasia, are a considerable source of human morbidity and mortality. Human primary intestinal culture is essentially not utilized as an experimental tool because primary tissue types lack appropriate in vitro culture methods. To meet this need, this project proposes to employ an innovative approach to enable the primary culture of three-dimensional 3-D human intestinal tissue, which is currently not possible.
The ability to reproducibly culture 3-D tissues outside of the body will enable scientists to test new hypotheses and models of physiology and disease, to develop high-throughput screens of pharmaceutical targets, and to enable the expansion of cells for regenerative medicine therapies. Hepatocyte transplantation has been reported as a possible therapeutic approach for liver disease; however, transplantation has been directed at the liver itself, limiting efficacy in patients with end-stage liver diseases, when cirrhosis and fibrosis are common.
This proposal will demonstrate that the generation of an ectopic liver within lymph nodes is an efficient method to restore hepatic function, highlighting the novel use of this organ as a site for hepatocyte transplantation. The project addresses some of the hurdles confronting the development of complex 3-D tissue models, and provides a new paradigm for tissue modeling, by using lymph nodes as in vivo bioreactors to grow tissue or organ substitutes.
Nitric Oxide NO is an essential signaling molecule for diverse physiological and disease processes. While the regulation of NO flux has focused primarily on the study of the three NO synthases NOS , their respective genetic deficiencies exhibit relatively modest phenotypes, which has led to difficulties in dissecting the specific cellular contributions to NO in different disease processes.
This project will study a new way that NO production may be regulated in the body by the chemical argininosuccinate lyase ASL which may control the production of arginine needed for NO production. The investigators will determine whether inhibiting ASL is the most effective way for controlling NO production in diseases affecting the brain, heart, and pancreas. The Hydroxylprolylproteome Grant ID: Posttranslational modifications of proteins play important roles in many signal transduction pathways, although the full extent to which these modifications impact cell function is not known.
Recent studies have highlighted a key role for a distinctive modification, prolyl hydroxylation, in the hypoxic response. This project seeks to develop novel capture reagents for a posttranslational modification, prolyl hydroxylation, that plays a central role in the oxygen- regulated turnover of Hypoxia Inducible Factor.
The long term goal will be to employ these reagents to determine the extent to which prolyl hydroxylation regulates the cellular hypoxic response, and to characterize changes in the hydroxylprolylproteome in response to differing oxygen concentrations.
These studies will have implications for understanding diseases such as heart attacks, stroke, and cancer that are characterized by hypoxia. Infectious disease is often untreatable, even when caused by a pathogen that is not resistant to antibiotics. This paradox could be explained by the fact that microbial populations produce persisters, dormant cells that are not mutants, but phenotypic variants of the wild type that are tolerant to antibiotics. The project will test the hypothesis that the agent responsible for untreatable infections is a super-persister cell which carries a high-persister mutation and has induced stress responses.
Mutants of the pathogens are able to enter into a state of dormancy highly tolerant to existing antibiotics. The findings are likely to change the way we view infectious diseases and provide rational approaches for discovering drugs that completely eradicate the infection. Until recently, small RNAs have been thought to function mainly as the mediators of an evolutionally conserved gene silencing mechanism known as RNAi. This application will establish a new paradigm of gene regulation mediated by small RNA that targets gene promoter sequence to induce potent and prolonged gene activation at the transcriptional level and in a sequence-specific manner, a phenomenon termed RNAa.
Despite the enormous potential for reprogramming gene expression in living cells, the molecular mechanism of RNAa is largely unknown and the rules for target selection are still quite obscure. Understanding the mechanism of RNAa will provide new insight to many physiological and diseases processes, may provide a tool to interrogate gene function and study their involvement in diseases, and may be a promising surrogate for traditional gene therapy for many diseases especially cancer.
Novel protein capture and detection reagents are required to understand comprehensively the interplay of the proteome in basic biological processes and in human health and disease.
These reagents need to have high affinity and specificity for particular protein targets, and they need to be easily created and produced, and be amenable to modification and immobilization for high throughput analysis of proteins. This project seeks to transform an existing technology to facilitate and streamline identification of novel capture reagents for human proteins and to incorporate these new reagents in assays that can accommodate simultaneous analysis of many proteins.
This project will not only develop new technology and assays that enable analysis of human proteins critical in human health and disease, but also generate the novel reagents that can be used for therapy.
Many diseases strike humans without obvious cause and, despite intense research, their etiology remains idiopathic. For example, it is likely that some idiopathic or autoimmune conditions or even cancers may be attributable to infectious agents even if conventional research avenues favor other mechanisms. The proposal will test the hypothesis that viral pathogens constitute the inciting events in aplastic anemia or other immune-mediated cytopenias, challenging the traditional understanding of autoimmunity in these specific conditions.
Contesting current theories of pathogenesis for such conditions may result in unexpected progress and new lines of scientific inquiry.
If infectious agents, likely viruses, can be identified, such a discovery would change the paradigm not only for these diseases but also for many other autoimmune diseases, and open avenues to prevention, diagnostics and effective treatments.
Chronic illness kills too many and costs too much. The current chronic illness system needs to be changed in order to deliver better care.
This project will join patients and physicians together in a collaborative innovation network to design, prototype and optimize, and evaluate a system for improving the chronic illness care system. If successful, this project will lead to improved care and self- management, better outcomes for people with chronic illness, and lower costs of care. This project will test the hypothesis that endogenous retroviruses, such as modern HERV-K HML-2 , can still replicate in modern humans using cutting-edge and complementary techniques.
Proving this hypothesis will be contrary to the entrenched dogma and have substantial implications for human genetics, cancer biology, and the safety of the human blood supply. One third of all individuals who develop colon cancer will die of metastatic spread of this disease. The classic genetic model for colon cancer development holds that colon cancer progression is due to accumulation of multiple gene mutations in the cancer cell.
This proposal advances the novel paradigm that cancer metastasis, the ultimate cause of death from this dread disease, is not due to new "metastasis-causing" gene mutations in the cancers, but rather is crucially depend on inborn genetic susceptibility factors. The import of this new paradigm for cancer metastasis will be felt in the identification of entirely new biological pathways that will be key to cancer management, to cancer prognosis, and to developing new and more effective anti-cancer therapies.
The ability of cells to form defined shapes, and to dynamically regenerate their cytoskeletal and membrane structures following damage, is one of the current mysteries of cell biology. Most studies of regenerative medicine have focused on developing methods to use stem cells to replace damaged cells. This proposal adopts an alternative approach using a classical model system, the giant ciliate Stentor, to study how injured cells repair themselves.
In addition to being a fundamental cell biological problem, understanding development and regeneration of cellular morphology would be a starting point for developing a whole new approach to regenerative medicine, in which rather than attempting to replace damaged cells with stem cell derived substitutes, one would induce the damaged cells to regenerate in situ. Brain function is dictated by its circuitry, yet we know little about its wiring architecture: The study of mouse models of neuropsychiatric disorders provides hope for the development of therapies for these burdensome illnesses, but progress has been slow due to the lack of knowledge about how the mouse brain is wired.
This project aims to close this gap by generating the first brain-wide wiring diagram of mouse, using automating techniques that are known to work but are labor-intensive. If successful, the project has the potential to fundamentally transform our understanding of brain function and brain disorders.
Mitochondrial number is very tightly regulated within the cell. Dysregulation of mitochondrial metabolism leads to decreased energy production, increased reactive oxygen species ROS , and altered apoptosis. These three factors play a role in a multitude of diseases, including heart disease, diabetes, cancer, obesity, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The project will investigate the way in which cells regulate the amount of mitochondria within a cell, with an eye towards their evolutionary origins.
The proposed research challenges the assumption that a traditional straightforward recitation of the facts is the optimal way to convey health-related information and empirically tests whether utilizing a narrative format might produce a greater and longer lasting impact on knowledge, attitudes and prevention behavior.
It also involves examination of the effect of communication modality i. Although the proposed research will focus on breast and cervical cancer, the results have clear implications for virtually all health care communication and could radically change how health messages are conveyed across different ethnic groups, generations and modalities.
Insulin Regulation of Monoamine Signaling: Pathway to Obesity Grant ID: Obesity and other dopamine-related pathologies such as schizophrenia, bipolar disorder, and attention-deficit disorder are a tremendous public health burden. Despite knowing better, we consume too many calories, too much fat, and too much sugar.
This proposal promises to transform our approach to this problem of obesity by analyzing how parallel changes in insulin and dopamine signaling, induced by high-fat feeding, cement changes in feeding behavior that lead to obesity and related co-morbidities. The finding may allow the development of new therapeutic interventions. There has been a 4-fold increase in obesity U. The dramatic rise in overweight and obesity over the last 40 years coincides with equally dramatic decreases in childhood infections.
Infections of childhood are disappearing due to changes in family size, improvements in hygiene, the addition of new vaccines, and other preventive health measures. This proposal seeks to determine whether the inverse trends of rising obesity and declining infection are coincidently related or causal.
This study intends to establish methods and collect preliminary data to determine whether decreases in childhood infection are linked to development of obesity. This project will test whether water plays a primary role in a number of representative biological systems, including osmosis and diffusion, surface tension and oxygen exchange, self-assembly, light-induced effects, vascular effects, and global health applications.
If the newly discovered features prove to be centrally relevant as hypothesized, then their relevance might extend more generally. If so, then this water-based approach may crack open the door to a new realm of biological understanding. The human liver serves as the reservoir for several important human pathogens, including hepatitis B HBV and C viruses HCV and Plasmodium species, all of which represent serious global health concerns.
A vaccine for HCV has not yet been developed, and, while HCV-specific protease and polymerase inhibitors are showing promise in early clinical development, rapid emergence of resistance indicates that additional targets and combinations of antivirals will be needed for effective control. The scarcity of in vitro and in vivo systems that faithfully mimic liver biology and susceptibility to human hepatotropic pathogens has severely hampered drug and vaccine development.
This project uses an interdisciplinary approach that combines tissue engineering with molecular virology and humanized mouse technology to create platforms that will facilitate studies of basic virus-host and virus-virus interactions, promote understanding of the mechanisms of liver disease progression, and provide predictive systems to test drug and vaccine efficacy and toxicity.
They will develop and apply this powerful new technology toward creating a comprehensive reagent set aimed at the Hepatitis C virus HCV proteome. Applying high- throughput approaches to create new protein capture reagents has the potential to speed the pace of proteomics research. The basic functions of many cell types are sensitive to physiological levels of mechanical forces acting on them and this phenomenon is always studied in the laboratory using monotonous mechanical stimuli.
However, cells in the body are exposed to irregularly varying stimuli and this variability may fundamentally alter all essential cell functions including secretion, growth and death. Uncovering how cells deal with such physiological variability may help understand how cells work in real living tissues as well as the pathogenesis of several major diseases including atherosclerosis, neuro-degenerative diseases, metabolic disorders, aging or cancer. RNA as a Hormone: The conventional paradigm of the endocrine system does not include RNA molecules as a class of hormones.
This proposal seeks to establish the new scientific paradigm that RNA molecules can function as hormones, traveling via the bloodstream to target organs where they are taken up and influence the activity of specific recipient cells. To establish this new paradigm, the researchers will focus on microRNAs secreted into the blood by cancer cells and use mouse models to determine whether the microRNAs are taken up by and influence distant organs and tissues.
Establishing this new paradigm will have a major impact not only on basic understanding of human physiology but could also open up new ways of diagnosing and treating disease based on RNA hormones in the blood. Whether fleeting or stable, normal or aberrant, protein interactions and their sites of contact form the basis for discovery of biological pathways, disease mechanisms, and opportunities for therapeutic intervention. Like the teeth of a key that perfectly fit into a lock, complementary protein shape is critical to the execution of biological interactions.
The goal of this proposal is to intertwine chemistry, biology, and medicine to create a transformative high- throughput technology that precisely identifies protein targets and their explicit sites of interaction. This new technology will address the current formidable challenge of identifying, distinguishing, and drugging the broad array of human protein targets. Not surprisingly, small-RNA therapeutics and biologic tools based on single gene interference are often plagued by "off-target" effects, resulting in poor therapeutic indices.
The approach holds promise for identifying and optimizing shRNA sequences for studies of stem-cell induction and cell differentiation, and for developing small RNAs to be used as therapeutics or biologic tools. Before human embryonic stem hES cell-based therapies for conditions such as neuronal disease, cardiovascular disease, diabetes, Parkinson's, and others can be translated to the clinic, new strategies are needed to overcome the immunological barrier to usage.
To address this critical bottleneck, this interdisciplinary team of investigators will develop novel and effective strategies to induce immunological tolerance for hES cell therapy. If successful, the project will represent a major scientific advancement in hES cell immunology and a significant step toward their eventual clinical translation.
Imaging the Invisible with No Labels: Small molecules such as metabolites and drugs are crucial to the biochemistry of living organisms but are difficult to study because they cannot be visualized easily in a living cell or organism. Label-free optical imaging based on Raman scattering is a highly desirable approach to use, but is limited by low sensitivity and long acquisition times.
This project team recently developed stimulated Raman scattering SRS microscopy which offers an unprecedented combination of high sensitivity, rapid image acquisition, chemical specificity and noninvasiveness. Studies of lipid metabolism and drug distributions in tissue are already underway in their laboratory.