1996 — 2000 |
Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
B1 Integrins Signaling During Cardiogenesis and Growth @ University of California Los Angeles
DESCRIPTION (adapted from the applicant's abstract): The proposed studies will examine the role of the integrin family of exctrcellular matrix (ECM) receptors in signalling between the ECM and the cell. While these receptors have been known for several years, their precise function(s) have only been theoretical. The proposed studies will address two hypotheses: 1) that the beta1 integrins are important signalling molecules with influence cardiac myofibrillogenesis and the induction of genes which define the hypertrophic myocyte phenotype; and 2) that the cytoplasmic domain of the beta1 provides a means to modulate ventricular chamber formation during cardiac development. To address these hypotheses 3 specific aims will examine: 1) the role of the beta1 cytoplasmic domain in signalling myocytes during cellular organization in the basal state, and during re-organization of the cell during stimulation of the spread/hypertrophic phenotype, in vitro; 2) how beta1 integrin cytoplasmic domain signaling influences normal cardiac development during early Murine cardiogenesis using an ex vivo murine embryo culture system and an ES/embryoid body system; and 3) evaluate the role of the beta1 integrin in cardiac chamber and outflow tract formation in vivo by using cardiac-specific expression of a dominant negative beta1 negative mutant transgenic mice.
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0.948 |
2001 — 2004 |
Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bi Integrins Signaling During Cardiogenesis &Growth @ University of California Los Angeles
DESCRIPTION (the applicant's description verbatim): The extracellular matrix and cytoskeleton are important in determining the function of the myocardium. Integrins are cell surface adhesive molecules, mechanotransduers, and transmit signals bi-directionally across the cell membrane, linking the extracellular matrix to the cytoskeleton. Beta-1 integrins are important components of hypertrophic signaling pathways and also in part determine normal cardiac function. The primary hypothesis of the current proposal is that beta-1 integrin expression and signaling influence growth and survival of the cardiac cell. To test this hypothesis, the following specific aims are proposed: 1) To assess the role of three alphabeta-1 integrin heterodimers and an integrin binding protein, in the hypertrophic and apoptotic responses of cultured ventricular myocytes. For these experiments recombinant adenoviral expression vectors and well characterized cardiac cell culture models of hypertrophy and apoptosis will be used. 2) To determine if apoptosis is the primary mechanism through which decreased beta-1 integrin protein expression in the murine cardiac myocyte leads to progressive fibrosis and heart failure. Mice have been constructed where the beta-1 integrin gene is disrupted only cardiac myocytes. The mechanism that causes progressive fibrosis and evolution of heart failure in these animals will be investigated. 3) To evaluate the role of the striated-muscle specific isoform of beta-1 integrin, termed beta-1D, as compared to the ubiquitously expressed beta-1A isoform, in defining normal function of the mature murine heart. A transgenic rescue approach will be used to restore cardiac myocyte expression of beta-lA or beta-1D integrin in the integrin deficient animals discussed in aim 2. 4) Investigate the morphological characteristics, integrin expression profile and integrin related signaling events, as well as extracellular matrix production of beta-1 integrin null cardiac fibroblasts as compared to wild-type fibroblasts, and fibroblasts that express only the beta-1A or beta-1D integrin isoforms. Beta-1 integrin null cardiac fibroblasts have been derived from our "floxed" mice. These cells will be characterized and then used to test the function of the ubiquitous (beta-1A) as compared to the striated muscle-specific (beta-1D) integrin isoforms. These studies will give us great insight into the function of beta-1A and beta-1D integrins in the normal and abnormal heart.
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0.948 |
2003 — 2006 |
Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vinculin and Metavinculin Function in the Myocardium @ Veterans Medical Research Fdn/San Diego
[unreadable] DESCRIPTION (provided by applicant): The cytoskeleton and actin-associated proteins provide for cellular structural integrity and function as a critical link between the extracellular matrix and the contractile apparatus of the myocyte. The focal adhesion is the intersection between the extracellular matrix and the cellular cytoskeleton, and may be a pivotal point for transmission of mechanical signals and organization of the actin based cytoskeleton. Vinuclin is a key focal adhesion protein. While vinculin is found in all cells, a muscle-specific splice variant termed metavinculin is found only in smooth and cardiac muscle. The biological role of metavinculin is poorly understood and its deficiency or mutation has been linked to human dilated cardiomyopathy. Homozygous vinculin knockout mice die by mid-gestation with severe neural and cardiac abnormalities via an unknown mechanism. Heterozygous vinculin knockout mice survive and breed normally but have abnormal cardiac function and die suddenly. It is possible that the cardiac abnormalities are due to direct affects of the vinculin deficiency in cardiac myocytes or related to alterations in non-cardiac cells. We hypothesize that normal vinculin expression in cardiac myocytes is crucial for appropriate cardiogenesis, cardiac myofibrillogenesis and function of the mature heart and that distinct biological functions of metavinculin exist. To test this we will manipulate vinculin and metavinculin in cultured cardiac myocytes and in the murine genome. Molecular, biochemical and immunocytochemical studies of cultured cells will be performed. Analysis of intact developing mice and the adult murine heart will likewise be evaluated by molecular, morphological, biochemical and physiological techniques. We propose the following specific aims: [unreadable] 1. Examine the role of vinculin in cardiogenesis and post-natal function of the heart by use of currently existing global vinculin "knockout" mice. [unreadable] 2. Study how deletion of the vinculin gene specifically in cardiac myocytes alters cardiac form and function. [unreadable] 3. Evaluate the biological function of the muscle-specific splice-variant metavinculin as distinct from vinculin, in cultured cardiac myocytes and the intact mouse. [unreadable] [unreadable]
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0.904 |
2006 — 2010 |
Ross, Robert Scott |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Mstp Summer Undergraduate Research Fellowship (Surf) @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): The Medical Scientist Training Program (MSTP) Summer Undergraduate Research Fellowship (SURF) was designed to attract and support underrepresented minority students interested in pursuing careers in biomedical research as a physician-scientist. The program is administered by the Medical Scientist Training Program (MSTP) within the School of Medicine and benefits by affiliation with campus wide Summer Programs at UCSD. The majority of training takes place on the UC San Diego campus, with affiliated faculty at the Salk Institute for Biological Studies and the Scripps Research Institute. The program provides an 8- week research oriented training experience and gives the students the opportunity to some exposure into a clinical setting. Students are selected for the program based on their academic record in a science-oriented curriculum and potential for success in a future physician-scientist program. Unique features of the MSTP SURF program include an emphasis on cardiovascular disease and exposure to career path of the physician-scientist. The specific aims of the training program will be to: 1) Recruit qualified applicants to the program; 2) Place selected trainees in supportive laboratories that are actively engaged in cardiovascular research; 3) Enable trainees to participate directly in a research project with appropriate supervision allowing hands-on involvement in experiments; 4) Provide group activities in concert with the integrated UCSD Summer Programs, including orientation to research and research ethics; 5) provide MSTP-SURF specific activities, including physician shadowing, shadowing MSTP students at the student-run free clinic, MSTP student research presentation and information on the MD/PhD pathway; 6) Provide trainees with constructive feedback on academic strengths and weaknesses and counseling regarding preparation for, Medical Scientist Training Programs or graduate school. [unreadable] [unreadable]
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0.949 |
2007 — 2011 |
Ross, Robert Scott |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Vinculin and Talin in Cardiocyte Integrity and Adhesion @ University of California San Diego
actin binding protein; laboratory mouse; sudden cardiac death
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0.949 |
2008 — 2011 |
Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Integrin Function in Cardiac Remodeling @ Veterans Medical Research Fdn/San Diego
[unreadable] DESCRIPTION (provided by applicant): Integrins are adhesive receptors and signaling molecules. Their role in the heart is poorly understood. 21 integrin is the dominant 2 integrin subunit expressed in cardiac myocytes and fibroblasts and partners with several 1 subunits in each of these cell types. The overall hypothesis of the current proposal is that cardiac myocyte and fibroblast integrins are critical organizers of signaling and structure within the heart. Knowledge of the function of these cellular receptors will allow us to establish a greater understanding of how the heart remodels following hemodynamic or ischemic stresses. Using unique mouse models and cells derived from them, this proposal will focus on three aims: 1) To determine the mechanism(s) for defective mechanical signaling and modulation of signaling crosstalk between integrin and G-protein coupled receptor pathways in the cardiac myocyte: focus on caveolae and focal adhesion proteins. Reduced 21 integrin expression in the cardiac myocyte leads to alterations in downstream signaling in heart subjected to pressure loading and in isolated myocytes stimulated with isoproterenol. We will test the hypothesis that reduction of myocyte integrins can alter mechanical and adrenergic signaling by disturbing multiple sub-cellular signaling integrators - e.g. focal adhesions and caveolae, and that disturbed downstream signaling may occur through both focal adhesion kinase dependent and independent pathways. 2) To evaluate the role of myocyte integrins in short-term ischemia / reperfusion and following myocardial infarction. Reduction of 21 integrins on the myocyte cell surface leads to abnormal functional responses of the heart subjected to ischemia / reperfusion while overexpression of integrins on the myocyte offers ischemic protection. In this aim the mechanism(s) which links integrin expression levels to myocardial ischemic dysfunction / protection will be evaluated using genetically manipulated mouse models where myocyte integrins are reduced or overexpressed. Work here will tie to studies of cardiac fibroblasts in aim 3. We hypothesize that integrin heterodimers modify membrane stability or myocyte signaling which alters responses of the heart to ischemia or infarction. 3) To assess the role of 21 integrins in cardiac fibrosis and fibroblast function: Fibrosis occurs in the murine heart with reduced myocyte expression of 21 integrin. This aim will determine the mechanism(s) which lead to this phenotype, particularly in the pathological heart (e.g. post-myocardial infarction) and study myocyte: fibroblast interactions. The hypotheses to be tested here will be that alteration of integrin expression on the myocyte leads to paracrine effects on the fibroblast and that altered 21 integrin expression levels on the fibroblast will functionally affect the fibroblast and potentially fibroblast- myofibroblast conversion. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
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0.904 |
2010 — 2014 |
Omens, Jeffrey H. [⬀] Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiomyocyte Mechanotransduction Through the Integrin Complex @ University of California San Diego
DESCRIPTION (provided by applicant): Mechanotransduction is the process by which cells sense external forces and respond with biological activity. In the myocardium, the cardiac myocytes are thought to sense and transmit forces both in and out of the cell through the integrin complex at the cellular membrane. This research will investigate the role of the membrane integrins and integrin-associated structural proteins within the cytoskeleton in force transmission. When these mechanical pathways are disrupted, cardiac dilation, diastolic dysfunction and heart failure can occur. There are there are two main pathways by which defects in the integrin complex results in dysfunction of the ventricle: first, the direct mechanical linkage between the extracellular matrix and the internal cytoskeleton can be defective, resulting in altered force transmission and hence diastolic dysfunction, and second, a defect in mechanosensing, from the outside in, will alter the hypertrophic and remodeling responses of the myocytes. We will investigate the significance of the integrin complex using mouse models with defective integrin and integrin-related proteins (vinculin and PINCH), which are thought to be critical components of stress sensing and force transmission at the cell membrane. The hypotheses that will be tested are (1) elastic recoil and diastolic relaxation of the left ventricle are modulated directly through mechanical linkages at the integrin complex;(2) Force transmission and mechanotransduction through the integrin complex are direction-dependent;(3) Function of the intracellular components of the integrin protein determines its mechanotransduction properties. To test these hypotheses, myocardial cells and tissues are used with state of the art experimental techniques, including magnetic resonance imaging, atomic force microscopy and isolated tissue testing, as well as cell- based functional assays. By understanding function of the proteins linked to mechanotransduction, we will advance our knowledge of the pathogenesis of cardiac hypertrophy, cardiomyopathy, the transition to heart failure and importantly, diastolic function of the myocardium. PUBLIC HEALTH RELEVANCE: This research examines the significance of forces transmitted into and out of cardiac myocytes, which play a significant role in remodeling responses of the heart tissue to overloads such as hypertension. Mouse models with defects in proteins responsible for mechanical force transmission will enable us to determine their role and how they can possibly be modified to prevent abnormal cellular and tissue responses leading the cardiac dilation and heart failure.
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0.949 |
2012 |
Ross, Robert Scott |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Replacement of Small Animal Echocardiographic Instrumentation @ Veterans Medical Research Fdn/San Diego
DESCRIPTION (provided by applicant): This proposal requests a small animal ultrasound imaging system to replace one with technology dating to 2002. The machine requested is a VisualSonics 2100 imaging system which has a new design compared to the older terminal technology. It is based on a digitally designed platform that is easily upgraded and functions at higher frame rates than the older machine. It also incorporates numerous new modes including color Doppler, simultaneous 2D and M-mode or 2D and Doppler imaging, steerable Doppler, strain and strain-rate imaging, automated ventricular analysis8 contrast imaging and ECG / respiratory gated imaging optimization software. It has a tremendous advance over the older technology since it uses solid state linear array ultrasound probes as opposed to mechanical probes. This allows for an electronically controlled, dynamically focused ultrasound beam as opposed to the single focal point on the older ultrasound probes. Higher quality and easier image acquisition results, permitting a higher throughput during an imaging session. Imaging artifacts are also reduced with the new probes vs. the older system, since they do not require maintenance. Due to design limitations, the older machine operated with technology many decades old in comparison to modern clinical ultrasound machines. The new machine brings great advances and advantages for small animal imaging. The importance of this technology can be appreciated since transgenic and knockout mice are now used quite commonly to facilitate understanding the molecular basis of disease. Yet, imaging of the heart, vessel or other organs in embryonic or adult rodents has lagged behind these molecular advancements, thus hindering our ability to assess the physiological relevance of the genetic manipulations. The requested instrument will enable us to: 1) perform serial in vivo measurements in living rodents and 2) obtain real-time spatial resolution that is nearly microscopic. Non-invasive in vivo assessment of the function of the mouse heart has been difficult because of both its small size and also since it beats at >600 times per minute. The requested instrument, for the first time, enables accurate assessment of not only whole heart function, but regional wall motion. This advancement will have profound implications on understanding the physiological importance of genetic manipulations in rodents. The information gained from these studies will yield important and novel data which will advance our knowledge about the basis for a wide range of disease processes and potentially lead to future novel therapies. Further, the imaging platform requested will allow us to equip our trainees for the highly desired ability to perform integrative studies on animal models, a capability that will make them more competitive in the academic marketplace. PUBLIC HEALTH RELEVANCE: The proposed instrument will be used to visualize the cardiovascular system and other organs in animals ranging in size from the smallest mouse embryo, to the size of an adult rat or guinea pig. Using harmless ultrasound, akin to that used to visualize the developing human fetus, it will allow the investigators to measure a large array of anatomic and functional attributes in the living animal, even at multiple time points.
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0.904 |
2013 — 2016 |
Ross, Robert Scott Roth, David M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Integrins and Caveolin Proteins in Cardiac Hypertrophy and Failure @ University of California San Diego
DESCRIPTION (provided by applicant): The mechanisms by which the cardiac myocyte (CM) senses mechanical changes and converts it to biochemical and functional effects, are poorly understood. Two areas within the CM that appear critical for proper mechanotransduction are the costamere with its resident integrins (ITGs), and caveolae, flask-shaped membrane invaginations with associated Caveolin (Cav) proteins. We and others have begun to show the importance of CM ITGs and Cav proteins in transducing mechanical signals, and that reduced expression and/ or mutation of ITGs and Cav3 can cause cardiomyopathies. How ¿1 ITGs and Cav-3 functionally interact and by what mechanisms their coordinated responses transduce mechanical signals in the CM are unknown. We have generated ¿1 ITG CM-specific knockout (KO) (termed ¿1cKO), Cav-3KO and CM-specific ITG and Cav-3 transgenic (Tg) mouse models. Our preliminary data shows that ¿1 ITG and Cav-3 co-localize and co-immunoprecipitate in the adult CM and that increased expression of ITGs and Cav-3 proteins in CMs can both preserve myocardial function when the heart is challenged with an increased mechanical load. Based on this data, we formulated our overall hypotheses that: A) ¿1 ITGs and Cav-3 have cooperative properties in organization of proteins required for CM mechanotransduction and B) that increased expression of both of these proteins in the CM will protect the heart challenged with an increased hemodynamic load from HF. We will pursue this with 3 aims using loss and gain of function approaches: 1) Determine roles of ¿1 ITGs and caveolin-3 in mechanotransductive responses of the myocardium by use of Cav3 null and ¿1 ITG cardiac myocyte specific knockout mice alone, or in combination. We will evaluate how acute and chronic mechanically mediated signals are altered when ITGs, Cav-3 or both proteins are lost from the CM and how loss of these proteins modifies the remodeling process as the heart hypertrophies and evolves towards a HF phenotype. 2) Define the interactions which direct cooperative mechanical signaling of cardiomyocyte ¿1 ITG and Cav-3. Direct interactions between ITGs and Cav3, with costameric and cytoskeletal proteins will be assessed. Proteomics will then identify novel proteins which interact with ITGs or Cav3, and how proteins in the caveolar and non-caveolar biochemical fraction of the CM change with hemodynamic challenge. 3) Determine how Tg overexpression of Cav-3 and/ or ¿¿1 ITGs alters mechanical responses, and delays or protects the heart from cardiac failure in the face of hypertrophic induction. This will allow us to directl test the potential therapeutic roles of Cav3 and ¿1 ITGs in the mechanically challenged myocardium. Clinical Significance: HF of varied causes is found in a large number of patients, necessitating frequent inpatient and outpatient care. Identification of root causes of cardiac dysfunction and importantly, studies which could lead to novel therapeutics of this common disease, are essential, and will be the focus of this proposal.
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0.949 |
2014 — 2018 |
Ross, Robert Scott |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Diversity in Research and Medicine @ University of California, San Diego
DESCRIPTION (provided by applicant): We propose here a new program at the UCSD School of Medicine (SOM) titled the Diversity in Research and Medicine (DIRM) Program. The goal of this short-term program is to introduce undergraduates who come from ethnic minorities, economically or socially disadvantaged backgrounds, as well as ones with physical disabilities to future training available in M.D./ Ph.D. programs, and attract them to a career as a physician-scientist. Individuals from all of these groups are underrepresented in medicine and biomedical sciences. Our overall goal is to provide a research-intensive but focused experience with exposure to critical components of the Physician-Scientist training program. The Specific Aims of the training program are to: 1) Provide a short-term research-intensive laboratory experience in the summer that will enable future participation in academic research efforts, and promote the entrance of individuals from underrepresented racial/ethnic or disadvantaged backgrounds into M.D./Ph.D. programs. 2) Enhance the ability of the applicants to understand the clinical training and efforts of physician-scientists by participation in a clinical shadowing experience with faculty members. 3) Motivate and enable trainees to apply to and matriculate in health science programs by participation in university-wide events and didactic conferences with faculty and MSTP trainees, culminating in written and oral presentation of the summer trainees' scientific work at a campus-wide forum for undergraduate trainees. The UCSD SOM has a long track record in research and clinical excellence, as well as experience in programs geared to amplifying the diversity of the biomedical workforce. The proposed DIRM Program will be connected to but distinct from our NIH-supported MSTP, a graduate-level program that trains M.D./Ph.D. physician- scientists. To qualify for DIRM, applicants must be undergraduate students from ethnic minority groups; economically or socially disadvantaged backgrounds or have a physical disability. The DIRM program is unique and significant in that it provides a research-intensive and clinically-connected program for these undergraduate trainees. Importantly, this program will be one of the few in the U.S that promotes both biomedical research and health care delivery and that focuses on future entrance into a M.D./Ph.D. program of students from backgrounds underrepresented in these programs. It will foster their future training and careers in biomedical sciences and healthcare, in general. By introducing such opportunities to these trainees who are at a formative age, we believe it will attract them towards a career as a physician-scientist with specific interest in cardiovascular diseases. We realize, of course, that it is difficult to predict this ultimate goal for students who are at an erly stage of their training, but our initial, preliminary results support this belief. (End of Abstract
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0.949 |
2015 — 2017 |
Ross, Robert Scott |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Cardiovascular Physiology & Pharmacology @ University of California San Diego
DESCRIPTION (provided by applicant): This proposal is for a long-standing, comprehensive, multidisciplinary program to train cardiovascular scientists in mechanisms of disease, and means to develop novel diagnostic and therapeutic approaches to cardiovascular illnesses. It focuses on the use of cellular, molecular, pharmacologic, physiologic and bioengineering approaches. The range of scientific disciplines in the training plan includes: 1) myocyte signaling and cell death, 2) cardiac development and regeneration, 3) the role of the extrasarcomeric cytoskeleton in cardiomyopathy, and 4) cardiac bioengineering. The proposal aims to continue with 2 pre-doctoral and 6 post-doctoral positions each year. The pre-doctoral training positions will draw from some of the best of a group of excellent students in the University of California, San Diego (UCSD) Biomedical Sciences, Bioengineering, and Medical Scientist Training (MSTP) programs. The postdoctoral positions are drawn from a large pool of Ph.D. postdoctoral fellows at UCSD, a Physician-Scientist Training Program (PSTP) in the Department of Medicine, and select cardiology fellows who demonstrate a strong interest in pursuing a career in cardiovascular science. The program aims to groom the trainees in acquisition of the knowledge and skills necessary to become independent investigators in cardiovascular research. At least two years of training will be required of all postdoctoral trainees. The Faculty of the program are from the Departments of Medicine, Pharmacology, Anesthesiology, School of Pharmacy and Bioengineering at UCSD and draw from the resources of the School of Medicine, School of Engineering, the Institute of Engineering in Medicine, the Cardiac Biological Science and Engineering Center, the new Sulpizio Cardiovascular Center, the Skaggs School of Pharmacy and Pharmaceutical Sciences and the Department of Veterans Affairs Medical Center. The program has both didactic and laboratory experiences. Most trainees will be cross-trained in several disciplines. Thoughtful career guidance will be a component of all stages of the program. Importantly, the training program will be tailored to meet each individual's specific long-term goals, to equip them best for a successful future in academic medicine and research. 117 trainees have received support from this training program since its inception in 1978. Almost 50% now hold positions as academic faculty with several serving in or having served in leadership positions. Another 30% have scientific positions in the biotechnology industry. Over the last 10 years, 81% of former trainees have continued to actively publish original work in journals cited by PubMed. This proposal will facilitate the continued pattern of success that has been established over the years. (End of Abstract)
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0.949 |
2015 — 2018 |
Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiac Myocyte Form and Function: Role of Talin and Kindlin @ University of California, San Diego
? DESCRIPTION (provided by applicant): Heart failure (HF) is a large and growing U.S. health problem with multifactorial origins, rare treatments of its root cause, and high 5-year mortality after diagnosis. Derangements in myocardial mechanosensing may lead to HF, yet how this process occurs in the cardiac myocyte (CM) remains poorly understood. Mechanotransduction is complex, requiring conversion of mechanical perturbations to biochemical and functional endpoints. In the CM it involves connections from the sarcolemma to the nucleus and requires a group of proteins in the costamere, including integrins (ITGs). ITGs act as adhesive receptors and signaling molecules, joining the extracellular matrix (ECM) to the cytoskeleton. My lab has studied the function of CM ITGs in transducing mechanical signals, and has shown that reduced expression and / or mutation of ITGs can cause cardiomyopathies. ITGs are bi-directional receptors. When they bind ECM ligands, activate downstream kinases and reorganize the cytoskeleton, it is termed outside-in signaling. In contrast, when intracellular events are triggered by receptors or pathways, unrelated to ITGs, they can produce conformational alterations in the ITG receptors leading to changes in their ligand (ECM) binding affinity, termed inside-out signaling. Increased ITG- ECM affinity has also been termed ITG activation. Two key CM costameric proteins which join to ITGs are Talin (Tln) and Kindlin (Kln). Both Tln and Kln have been suggested to be important for ITG activation from general work in cells such as fibroblasts or platelets, but their mechanistic function has not been studied previously in CMs. Two Tln isoforms, Tln1 and Tln2, are produced. In addition, there are 3 Kln forms, with the dominant CM Kln protein being Kln2. Tln1, Tln2 and Kln2 are all expressed in the human CM and Tln1 is significantly upregulated in human dilated cardiomyopathy. To begin study of Tln and Kln in CMs, we have generated knockout (KO) mouse models including Tln1 CM-specific KO, Tln2KO, and Kln2 CM-specific KO. Using these models we formulated our overall hypotheses that Tln and Kln2 proteins provide unique roles in cardiac form and function, specifically regulating ITG activation and transmission of mechanical signals within the CM, and that altered expression of Tln may protect the stressed myocardium. We will test this global hypothesis with 3 aims: 1) evaluate the hypotheses that Talin-1 and Talin-2 are essential for myocyte and whole heart function, mechanical signaling and integrin activation. 2) Critically examine the hypothesis that expression of Kindlin-2 is required for normal myocardial development and function of the mature heart. 3) Examine how Talin can be cardioprotective against hemodynamic stress. The proposal is significant since it will advance our understanding of the molecular basis of cardiomyopathies, allow a greater understanding of CM mechanical signaling and with this lead to potential novel HF therapies.
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0.949 |
2018 — 2021 |
Chen, Ju Ross, Robert Scott |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Cardiovascular Physiology and Pharmacology @ University of California, San Diego
Summary: This proposal is a competitive renewal of an NHLBI-sponsored training grant that has been funded continuously for almost four decades and has trained most of the trainees in cardiovascular biology at our university, since its inception. We request support for eight Postdoctoral trainees. Given our UCSD environment and faculty with common interests as well as a breadth of expertises, the major objective of our program is to train individuals so that they have a broad-based background in cardiovascular biology, but a focused research direction in the study of cardiovascular development, physiology and disease. The specific scientific disciplines that are included in the training plan are 1) cardiac signaling, 2) cardiac development, cardiac regeneration and stem cell biology, 3) cardiac genetics and epigenetics and 4) cardiac bioengineering. This program provides extensive mentoring of trainees, to equip them to become independent investigators and remain in academic positions, or have success with careers in industry, government or non-profit sector biomedical positions. The Postdoctoral positions are drawn from a large pool of fellows that apply directly to our faculty, or from applicants to our Cardiovascular Medicine fellowship or Physician-Scientist Training Program (a ?short-track? pathway program for M.D./Ph.D. trained medical students to enter internal medicine residency and be assured acceptance to the Cardiovascular Medicine fellowship,) who show a strong interest in pursuing a career in cardiovascular science. Since its beginning in 1978, 130 trainees have received support from this program and a large majority of them hold independent positions in biomedicine as either academic faculty, or positions in research oriented fields, with most remaining active in research and publishing regularly. At least two years of training will be required of all trainees. Our 23 excellent faculty are from: The Departments of Anesthesiology, Bioengineering, Medicine, and Pharmacology, as well as the School of Pharmacy & Pharmaceutical Sciences. The program is composed of both didactic and laboratory experiences and emphasizes bench and career oriented training. At all stages of the program career planning will be stressed and the training program tailored to meet an individual trainee's long-term goals in academic medicine, biomedical fields and research.
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0.949 |
2019 — 2021 |
Reznik, Vivian Ross, Robert Scott Trejo, Joann [⬀] |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Ucsd Pride Faculty Development Program in Cardiovascular Sciences @ University of California, San Diego
Abstract/Summary The UCSD PRIDE Faculty Development Program in Cardiovascular Sciences (FDP-CVS) will recruit and engage underrepresented early career junior faculty and transitioning postdoctoral fellows that have secured an initial faculty position in activities to enhance critical academic skills in cardiovascular research and to increase their success in obtaining NIH or equivalent funding. We will recruit 4 cohorts of 8 scholars to participate in a 2-week Summer Institute, followed by a mid-year 2-3 day meeting and second 1-week Summer Institute at UCSD. FDP- CVS will utilize evidence-based strategies to enhance professional development, research education, grantsmanship skills and effective mentoring. FDP-CVS is directed by three PIs with a history of mentoring and training students, fellows and junior faculty and success in creating and implementing career development and mentoring programs specifically for underrepresented minority (URM) trainees. All PIs have successfully led extramurally-funded training programs; two of the three PIs are actively engaged in NIH-sponsored cardiovascular research and one PI is from a URM background. The overall goal of the FDP-CVS is to enhance the diversity of investigators working in biomedical and clinical research in cardiovascular science. The specific objectives of the UCSD FDP-CVS are to increase the representation of individuals from underrepresented racial/ethnic and disabled groups in obtaining NIH or equivalent funding. We propose three specific aims. Aim 1 will identify and nationally recruit promising underrepresented early career junior faculty as well as transitioning postdoctoral fellows that have expertise and research interests aligned with UCSD research mentors. Aim 2 will use evidence-based strategies to enhance professional development and effective mentorship to underrepresented early career junior faculty and transitioning postdoctoral fellows. FDP-CVS will utilize new and existing paradigms to establish long-term mentoring relationships between early career junior faculty and transitioning postdoctoral fellows, senior faculty mentors at their home institution and career and expert research mentors at UCSD. Aim 3 will enhance self-efficacy in research and success in obtaining NIH or equivalent funding of underrepresented early career junior faculty and transitioning postdoctoral fellows, we use evidence- based strategies to enhance the development of robust research programs in the mentees area of interest and provide skills to enhance grant writing and networking to facilitate success in obtaining extramural funding for these research programs. UCSD FDP-CVS includes three PIs with experience in faculty and URM trainee development, a cohort of senior faculty mentors with expertise in cardiovascular research and strong track record in obtaining NIH funding, faculty career mentors from underrepresented backgrounds and a robust evaluation and dissemination plan.
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0.949 |
2020 — 2021 |
Cho, Yoshitake Ross, Robert Scott |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Perm in Cardiac Function @ University of California, San Diego
Cardiac contraction requires a high and reliable flux of ATP as energetic deficiencies lead to disease, as seen in humans with mutations in mitochondrial DNA or nuclear-encoded respiratory genes. This is supported by mouse models with mutations in genes of oxidative metabolism. Cardiac energy metabolism and, in particular, the high capacity for ATP production are controlled by a network of transcriptional regulators, including the coactivators PGC-1? and PGC-1?, and the orphan nuclear receptors ERR? and ERR?. This network regulates genes important for mitochondrial biogenesis, oxidative metabolism and thus contraction of cardiac myocytes (CM). PGC-1/ ERR complexes act directly on many target genes, but also activate downstream transcription factors that amplify and/or extend their scope of action. Elucidation of such PGC-1/ERR downstream effectors can reveal novel molecules that impact heart bioenergetics and that could be used to beneficially modify cardiac energy state. Here, we will elucidate the role of a novel gene, PERM1, in cardiac energy metabolism. We identified it as a gene induced by PGC-1?/? and ERR?/?/????and found it expressed specifically in tissues with high-energy demand, such as heart and skeletal muscle, and induced in vivo by signals known to activate PGC-1?. We hypothesize that PERM1 acts with PGC-1 and ERR factors in controlling the expression of genes important for mitochondrial biogenesis and ATP production, thereby protecting the heart from heart failure induced by pressure overload and ischemia reperfusion injury. Three aims will test this hypothesis: Aim 1. Study of the metabolic pathways regulated by Perm1 in cardiomyocytes (CM). This aim will study metabolic pathways regulated by Perm1 in cultured CM to evaluate the hypothesis that Perm1 modulates Mito biogenesis and cellular metabolic pathways in the CM. It will pursue the involvement of PGC-1/ERR in Perm1 function, and also evaluate mechanism(s) by which Perm1 modulates PGC-1/ERR activity using directed and unbiased approaches, including metabolomics. Aim 2. Determine the role of Perm1 in pressure overload-induced HF. We will focus on the role of Perm1 in the heart subjected to hemodynamic stress, and assess its role as the heart undergoes evolution from compensated hypertrophy to HF. For this we use mouse models (in hand) which direct CM-specific overexpression and ablation (knockout (KO)) of Perm1 expression ? (termed Perm1cTg and Perm1cKO, respectively). Aim 3. Evaluate the role of Perm1 in providing cardiac protection from deleterious effects of ischemia and ischemia-reperfusion (IR) injury. We will study the role of Perm1 in ischemic injury also using our unique mouse models, given the hypothesis that Perm1cTG-mediated overexpression will be cardioprotective in the ischemic heart, while Perm1cKO will produce deleterious responses in ischemic- challenged hearts. We expect this work to define PERM1 as a regulator of cellular bioenergetics and potentially provide a new target for therapeutic pathways that are applicable to treatment of heart failure.
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