2009 — 2015 |
Bruneau, Benoit Gaetan (co-PI) [⬀] Conklin, Bruce R (co-PI) [⬀] Srivastava, Deepak [⬀] Yamanaka, Shinya |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. U01Activity 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. |
Induced Pluripotent Stem Cells in the Understanding and Treatment of Heart Diseas @ J. David Gladstone Institutes
DESCRIPTION (provided by applicant): Over 1 million Americans suffer acute myocardial infarctions each year in the US, and among the survivors there are now 5 million with heart failure. In addition, defects in cell lineage determination or morphogenesis underlie congenital heart malformations, the most common human birth defect. Survivors of congenital heart disease, which number over 1 million in the US, also often suffer from heart failure. Unfortunately, the heart has little, if any, regenerative capacity after injury. The recent technology of human induced pluripotent stem (iPS) cells, developed by Dr. Shinya Yamanaka, has opened the door for novel approaches to human disease. These include the development of human cellular models for understanding disease mechanisms and drug discovery, along with the potential for autologous cell-based therapies. iPS cells are reprogrammed somatic cells that have properties very similar to embryonic stem (ES) cells and potentially provide an alternative to human ES cells for therapy. However the current methods of iPS generation involve viral integration into the genome, precluding their use in humans. We have assembled a team of investigators to develop and capitalize on the potential of induced pluripotent stem cells (iPS) in the treatment of heart disease. These include Drs. Deepak Srivastava, Shinya Yamanaka, Benoit Bruneau and Bruce Conklin, who together bring expertise in the areas of pluripotency, cardiac differentiation, signaling and human genetics. The multiple PIs will work together to address the specific aims with overlap of expertise from several PIs within each aim. This multidisciplinary approach will combine strengths in iPS technology with leaders in microRNA, chromatin remodeling and signaling as they relate to cardiac cell fate and cardiac disease. The specific aims of the proposal are: 1) To develop integration-free methods of human iPS cell generation for future cell-based therapies;2) To develop efficient directed differentiation of human iPS cells and methods of direct reprogramming into cell types relevant for future cell-based therapies directed at cardiovascular disease;and 3) to use iPS technology for discovery of human cardiovascular disease mechanisms and for drug discovery approaches. The integrated team assembled in this proposal will bring broad and critical expertise to the NHLBI Progenitor Cell Consortium in an effort to aggressively capitalize on the promise and potential of iPS cells for heart disease.
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0.901 |
2009 — 2014 |
Boyer, Laurie A (co-PI) [⬀] Bruneau, Benoit Gaetan [⬀] Conklin, Bruce R (co-PI) [⬀] Pollard, Katherine Snowden (co-PI) [⬀] Srivastava, Deepak (co-PI) [⬀] Yamanaka, Shinya |
U01Activity 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. |
The Epigenetic Landscape of Heart Development @ J. David Gladstone Institutes
DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are among the most common and most devastating birth defects in humans. Networks of transcription factors regulate cardiac cell fate and morphogenesis, and dominant mutations in transcription factor genes lead to most instances of inherited CHD. The mechanisms underlying CHDs that result from disruption of these networks remain to be identified, but regulation of gene expression within a relatively narrow developmental window is clearly essential for normal cardiac morphogenesis. In addition to transcription factors, epigenetic regulation via histone modifications, chromatin remodeling, and non-coding RNAs have key roles in modulating gene expression programs. Elucidating on a genome scale the physical and functional interactions between transcription factors and epigenetic regulators will considerably enhance our understanding of the control of heart development and will have important implications for understanding the mechanistic basis of CHDs. We propose a project as part of the NHLBI Heart Development consortium to provide an integrated epigenetic landscape for heart development, with a focus on CHD-related genes. We propose three major aims. Aim 1: Define genome-wide occupancy maps of transcription factors with known roles in cardiac development and human disease, and epigenetic regulators of transcription, in differentiating cardiomyocytes. Aim 2: Define the global function of transcriptional and epigenetic regulation in heart development and congenital heart disease. We will examine the effect of loss of function of cardiac transcription factors on epigenetic regulation, and alterations in epigenetic regulation in disease-specific induced pluripotent cells from CHD patients. We will also evaluate the global role of histone modifications in mouse heart development. Aim 3;Integrate microRNA expression and function into the regulatory networks governing cardiac development. High-resolution occupancy maps from Aims 1 and 2 will be analyzed specifically for miRNA promoter occupancy and combined with quantitative sequencing of miRNAs in differentiating cardiomyocytes. We will study the function of highly altered miRNAs, specifically those that target disease-causing cardiac transcription factors. Our studies will yield an important and transformative epigenetic atlas of heart development, which will link for the first time transcriptional and epigenetic regulators in a comprehensive network that will illuminate mechanisms underlying CHDs. RELEVANCE (See instructions): The proposed project will for the first time allow a new understanding of the gene networks that underlie congenital heart disease. Congenital heart disease is the most serious childhood illness, affecting 1% of children, and leading to significant mortality and long-term illness. However the underlying causes of these diseases are not understood. Our project will link the so-called "epigenetic regulators" that control how genes are turned on or off, to congenital heart disease, bringing new important insights into these diseases.
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0.901 |