This is a competitive renewal application to study the role an atypical homeodomain protein called Hopx that is expressed in the heart. My laboratory discovered Hopx about 10 years ago, and we have shown that it functions, at least in part, by recruiting histone deacetylases (HDACs) to transcription complexes. This work, funded by this grant, led to numerous high-profile publications, patent applications, and it has spurred our efforts in collaboration with the private sector to translate the findings and bring new therapies for heart failure to the clinic. Our mechanistic studies have shown that Hopx does not bind directly to DNA, but that it is a component of cardiac repressor complexes. Hopx is expressed by cardiac progenitor cells at early time-points of murine embryogenesis, just after Nkx2-5, at ~E8.0, and inactivation of Hopx leads to partially penetrant embryonic lethality and thin myocardium. Cardiac progenitors that express Nkx2-5 are multipotent and can produce myocardial, smooth muscle or endothelial lineages. However, Hopx-expressing progenitors are committed to the myocardial lineage. Our data suggest that fate decisions of cardiac precursor cells are biased by Hopx dose and activity. We hypothesize that Hopx is an extremely early (perhaps the earliest) marker of committed myocardial cells and that Hopx functions to reinforce the myocardial lineage choice by recruiting HDACs and other transcription cofactors to repress critical mediators of alternate fates and of the multipotent state. Understanding how myocardial fate decisions are executed and reinforced will inform our ability to enhance regenerative therapies and instruct stem and progenitor cells to produce functional myocardium.

Public Health Relevance

This project focuses on the regulation of expansion and differentiation of cardiac progenitor cells, which produce many of the cell types found in the adult heart including cardiac myocytes, smooth muscle and endothelial cells. The discovery of mechanisms to regulate expansion and differentiation of cardiac progenitor cells will enhance our ability to promote regenerative therapies for heart failure and heart attack patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071546-13
Application #
9252508
Study Section
Special Emphasis Panel (ZRG1-CVRS-P (02))
Program Officer
Schramm, Charlene A
Project Start
2003-09-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
13
Fiscal Year
2017
Total Cost
$394,588
Indirect Cost
$144,588
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit et al. (2017) Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171:573-587.e14
Loh, Kyle M; Chen, Angela; Koh, Pang Wei et al. (2016) Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types. Cell 166:451-467
Li, Deqiang; Takeda, Norifumi; Jain, Rajan et al. (2015) Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res 15:522-529
Jain, Rajan; Barkauskas, Christina E; Takeda, Norifumi et al. (2015) Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun 6:6727
Jones, Andrew; Opejin, Adeleye; Henderson, Jacob G et al. (2015) Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression. J Immunol 195:1489-97
Jain, Rajan; Li, Deqiang; Gupta, Mudit et al. (2015) HEART DEVELOPMENT. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Science 348:aaa6071
Zhou, Xiaoying; Crow, Amanda L; Hartiala, Jaana et al. (2015) The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice. Stem Cell Reports 5:125-38
Li, Ning; Yousefi, Maryam; Nakauka-Ddamba, Angela et al. (2014) Single-cell analysis of proxy reporter allele-marked epithelial cells establishes intestinal stem cell hierarchy. Stem Cell Reports 3:876-91
Takeda, Norifumi; Jain, Rajan; Leboeuf, Matthew R et al. (2013) Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells. Development 140:1655-64
Singh, Nikhil; Gupta, Mudit; Trivedi, Chinmay M et al. (2013) Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression. Dev Biol 377:333-44

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