Neil C Chi
University Of California San Diego
Project start date: 2011-07-01
Project end date: 2015-06-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Neil C Chi
Zebrafish Heart Mutants:Physiological& Genetic Analyses
Neil C Chi
University Of California San Francisco 3333 California St., Ste 315 San Francisco, Ca 941430962
Grant 5K08HL074891-03 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The broad objectives of this proposal are to discover new cellular and molecular pathways of cardiovascular pathologies utilizing zebrafish, a model genetic vertebrate system. The proposed research describes a five-year training plan for the development of an academic career in cardiovascular medicine. This training will be conducted within the highly collegial and scientific environment at the University of California, San Francisco (UCSF). The principal investigator, Dr. Chi, is currently a cardiology fellow in the American Board of Internal Medicine Clinical Investigator Pathway Program at UCSF. He has a firm commitment to becoming a physician-scientist as evidenced by his previous record. The candidate s long-term goals are to establish an investigative research career studying environmentally and genetically acquired heart disease. The comprehensive career development plan incorporated includes mentorship by a scientific advisor and advisory committee; participation in relevant course work, seminars, and scientific retreats both locally and nationally; and an academic appointment providing protected research time to ensure his success in achieving his career goals. The translucent nature of the zebrafish organism allows for easy large-scale mutagenesis screens identifying a diverse array of novel cardiovascular anatomic and physiologic phenotypes. Interestingly, two of these physiologic cardiovascular mutants, pickwick (pik/ttn) and silent heart (sih/tnnt2), have been found to be linked to human cardiomyopathies. However, a piethora of cardiovascular physiologic zebrafish mutants displaying phenotypes similar to other known human cardiovascular disorders remain physiologically and genetically uncharacterized. These mutations can be divided into two subgroups, one of which the contractility of the heart is affected (cardiomyopathies) and the other in which the rhythm of the heart beat is abnormal (arrhythmias). We hypothesize that detailed genetic and physiologic analysis of cardiovascular zebrafish mutants most similar to known human cardiovascular disorders may lead to the discovery of novel cellular and molecular pathophysiologic mechanisms of human cardiac arrhythmias and heart failure. Thus, we propose the following specific aims 1) To rapidly identify physiologic zebrafish cardiovascular mutants from a forward genetic screen by light microscopy; 2) To perform detailed physiologic, cellular and molecular analysis on those identified mutants from Specific Aim 1; 3) To focus and identify the mutant genes for those mutants whose phenotype most resemble human cardiovascular disorders as characterized by Specific Aim 2. These zebrafish mutants ultimately may serve as a novel gateway to gain new insight into the cellular and molecular mechanisms of human cardiac arrhythmias and heart failure.
Keywords: arrhythmia, gene mutation, heart failure, molecular pathology, mutant, myocardium disorder, pathologic process, cardiac myocyte, cellular pathology, gene complementation, genetic model, heart contraction, heart rhythm, hemodynamics, model design /development, phenotype, electrocardiography, electrophysiology, genetic screening, genetically modified animal, immunocytochemistry, in situ hybridization, light microscopy, molecular cloning, transmission electron microscopy, zebrafish
Project start date: 2004-03-01
Project end date: 2009-02-28
5K08HL074891-03 (2006): $121770
5K08HL074891-02 (2005): $121770
Zebrafish Heart Mutants:Physiological And Genetic Analyses
Neil C Chi
University Of California San Francisco 3333 California St., Ste 315 San Francisco, Ca 941430962
Grant 1K08HL074891-01 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The broad objectives of this proposal are to discover new cellular and molecular pathways of cardiovascular pathologies utilizing zebrafish, a model genetic vertebrate system. The proposed research describes a five-year training plan for the development of an academic career in cardiovascular medicine. This training will be conducted within the highly collegial and scientific environment at the University of California, San Francisco (UCSF). The principal investigator, Dr. Chi, is currently a cardiology fellow in the American Board of Internal Medicine Clinical Investigator Pathway Program at UCSF. He has a firm commitment to becoming a physician-scientist as evidenced by his previous record. The candidate s long-term goals are to establish an investigative research career studying environmentally and genetically acquired heart disease. The comprehensive career development plan incorporated includes mentorship by a scientific advisor and advisory committee; participation in relevant course work, seminars, and scientific retreats both locally and nationally; and an academic appointment providing protected research time to ensure his success in achieving his career goals. The translucent nature of the zebrafish organism allows for easy large-scale mutagenesis screens identifying a diverse array of novel cardiovascular anatomic and physiologic phenotypes. Interestingly, two of these physiologic cardiovascular mutants, pickwick (pik/ttn) and silent heart (sih/tnnt2), have been found to be linked to human cardiomyopathies. However, a piethora of cardiovascular physiologic zebrafish mutants displaying phenotypes similar to other known human cardiovascular disorders remain physiologically and genetically uncharacterized. These mutations can be divided into two subgroups, one of which the contractility of the heart is affected (cardiomyopathies) and the other in which the rhythm of the heart beat is abnormal (arrhythmias). We hypothesize that detailed genetic and physiologic analysis of cardiovascular zebrafish mutants most similar to known human cardiovascular disorders may lead to the discovery of novel cellular and molecular pathophysiologic mechanisms of human cardiac arrhythmias and heart failure. Thus, we propose the following specific aims 1) To rapidly identify physiologic zebrafish cardiovascular mutants from a forward genetic screen by light microscopy; 2) To perform detailed physiologic, cellular and molecular analysis on those identified mutants from Specific Aim 1; 3) To focus and identify the mutant genes for those mutants whose phenotype most resemble human cardiovascular disorders as characterized by Specific Aim 2. These zebrafish mutants ultimately may serve as a novel gateway to gain new insight into the cellular and molecular mechanisms of human cardiac arrhythmias and heart failure.
Keywords: arrhythmia, gene mutation, heart failure, molecular pathology, mutant, myocardium disorder, pathologic process, cardiac myocyte, cellular pathology, gene complementation, genetic model, heart contraction, heart rhythm, hemodynamics, model design /development, phenotype, electrocardiography, electrophysiology, genetic screening, genetically modified animal, immunocytochemistry, in situ hybridization, light microscopy, molecular cloning, transmission electron microscopy, zebrafish
Project start date: 2004-03-01
Project end date: 2009-02-28
1K08HL074891-01 (2004): $120090
Heart Mutants:Physiological& Genetic Analyses
Neil C Chi
Medicineuniversity Of California San Francisco, 3333 California St., Ste. 315, San Francisco, Ca 941430962
Grant 5K08HL074891-04 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The broad objectives of this proposal are to discover new cellular and molecular pathways of cardiovascular pathologies utilizing zebrafish, a model genetic vertebrate system. The proposed research describes a five-year training plan for the development of an academic career in cardiovascular medicine. This training will be conducted within the highly collegial and scientific environment at the University of California, San Francisco (UCSF). The principal investigator, Dr. Chi, is currently a cardiology fellow in the American Board of Internal Medicine Clinical Investigator Pathway Program at UCSF. He has a firm commitment to becoming a physician-scientist as evidenced by his previous record. The candidate´s long-term goals are to establish an investigative research career studying environmentally and genetically acquired heart disease. The comprehensive career development plan incorporated includes mentorship by a scientific advisor and advisory committee; participation in relevant course work, seminars, and scientific retreats both locally and nationally; and an academic appointment providing protected research time to ensure his success in achieving his career goals.The translucent nature of the zebrafish organism allows for easy large-scale mutagenesis screens identifying a diverse array of novel cardiovascular anatomic and physiologic phenotypes. Interestingly, two of these physiologic cardiovascular mutants, pickwick (pik/ttn) and silent heart (sih/tnnt2), have been found to be linked to human cardiomyopathies. However, a piethora of cardiovascular physiologic zebrafish mutants displaying phenotypes similar to other known human cardiovascular disorders remain physiologically and genetically uncharacterized. These mutations can be divided into two subgroups, one of which the contractility of the heart is affected (cardiomyopathies) and the other in which the rhythm of the heart beat is abnormal (arrhythmias). We hypothesize that detailed genetic and physiologic analysis of cardiovascular zebrafish mutants most similar to known human cardiovascular disorders may lead to the discovery of novel cellular and molecular pathophysiologic mechanisms of human cardiac arrhythmias and heart failure. Thus, we propose the following specific aims 1) To rapidly identify physiologic zebrafish cardiovascular mutants from a forward genetic screen by light microscopy; 2) To perform detailed physiologic, cellular and molecular analysis on those identified mutants from Specific Aim 1; 3) To focus and identify the mutant genes for those mutants whose phenotype most resemble human cardiovascular disorders as characterized by Specific Aim 2. These zebrafish mutants ultimately may serve as a novel gateway to gain new insight into the cellular and molecular mechanisms of human cardiac arrhythmias and heart failure.
Keywords: arrhythmia, gene mutation, heart failure, molecular pathology, mutant, myocardium disorder, pathologic processcardiac myocyte, cellular pathology, gene complementation, genetic model, heart contraction, heart rhythm, hemodynamics, model design /development, phenotypeelectrocardiography, electrophysiology, genetic screening, genetically modified animal, immunocytochemistry, in situ hybridization, light microscopy, molecular cloning, transmission electron microscopy, zebrafish
Project start date: 2004-03-01
Project end date: 2009-02-28
5K08HL074891-04 (2007): $121770
DIRECTED CARDIAC CELLULAR PROGRAMMING: A NEW PARADIGM FOR CARDIAC REGENERATION
Neil C Chi
University Of California San Diego, 9500 Gilman Dr, Dept 0934, La Jolla, Ca 92093-0934
Grant 1DP2OD007464-01 from Office Of The Director, National Institutes Of Health
Abstract: Nearly 5 million people in the US are afflicted with heart failure with an additional 550,000 new cases diagnosed each year. Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in the US and developed world because of the failure to adequately replace lost ventricular myocardium from ischemia-induced infarct. Though cell-based therapies to repair the heart have been attempted, they currently have not resulted in long-term improvement due to the inability of human pluripotent stem cells or cardiac progenitor cells to fully differentiate into mature and functional ventricular cardiomyocytes for human cardiac regenerative repair. Toward this end, we have discovered a novel and exciting paradigm for cardiac regeneration that involves cardiac reprogramming and transdifferentiation. Further mechanistic insight into this biologic process will provide an innovative approach to the long-standing issue of programming potential cellular regenerative sources into functional ventricular myocardium for human cardiac regeneration. Thus, utilizing a multi-disciplinary and translational approach, I propose to build from our exciting results and develop novel strategies towards further understanding the fundamental mechanisms of cardiac transdifferentiation with the eventual goal of applying these insights for directed human cardiac cellular programming. These approaches have the real potential to not only revolutionize our understanding of cardiac cellular programming but also provide a safer and more functional source of ventricular myocardial replacement for injured ventricles in heart failure patients. Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in the US and developed world because of the failure to adequately replace lost ventricular myocardium from ischemia-induced infarct. Though cell-based therapies to repair the heart have been attempted, they currently have not resulted in long-term improvement due to the inability of human pluripotent stem cells or cardiac progenitor cells to fully differentiate into mature and functional ventricular cardiomyocytes for human cardiac regenerative repair. Thus, utilizing a multi-disciplinary approach, I propose to build from our new cardiac transdifferentiation paradigm and develop novel strategies towards further understanding the fundamental mechanisms of this biologic event with the eventual goal of applying these insights for directed human cardiac cellular programming
Keywords: Cardiac; Cardiac Myocytes; Cardiocyte; Cell Therapy; Diagnosis; FLR; Failure (biologic function); Goals; Heart; Heart failure; Heart myocyte; Human; Human, General; Infarction; Ischemic Heart; Ischemic Heart Disease; Ischemic myocardium; Man (Taxonomy); Man, Modern; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Mother Cells; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle, Cardiac; Muscle, Heart; Myocardial; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Natural regeneration; Patients; Pluripotent Stem Cells; Process; Progenitor Cells; Programs (PT); Programs [Publication Type]; Protocols, Treatment; RGM; Regeneration; Regimen; Source; Stem cells; Therapy, Cell; Treatment Protocols; Treatment Regimen; Treatment Schedule; Ventricular; ing; cardiac failure; cardiac muscle; cardiomyocyte; cell-based therapy; failure; heart ischemia; heart muscle; infarct; injured; innovate; innovation; innovative; insight; myocardial ischemia/hypoxia; myocardium ischemia; new approaches; novel; novel approaches; novel strategies; novel strategy; programs; regenerate; regenerative; repair; repaired; transdifferentiation; translational approach
Project start date: 2010-09-30
Project end date: 2015-08-31
Budget start date: 30-SEP-2010
Budget end date: 31-AUG-2015
PFA/PA: RFA-RM-09-011
1DP2OD007464-01 (2010): $2322250