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 #
2R01HL071546-10
Application #
8729690
Study Section
Special Emphasis Panel ()
Program Officer
Schramm, Charlene A
Project Start
2003-09-01
Project End
2018-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
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
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
Banerjee, Audreesh; Trivedi, Chinmay M; Damera, Gautam et al. (2012) Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 46:132-8
Trivedi, Chinmay M; Cappola, Thomas P; Margulies, Kenneth B et al. (2011) Homeodomain only protein x is down-regulated in human heart failure. J Mol Cell Cardiol 50:1056-8
Singh, Nikhil; Trivedi, Chinmay M; Lu, MinMin et al. (2011) Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract. Circ Res 109:1240-9
Sun, Zheng; Singh, Nikhil; Mullican, Shannon E et al. (2011) Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J Biol Chem 286:33301-9
Takeda, Norifumi; Jain, Rajan; LeBoeuf, Matthew R et al. (2011) Interconversion between intestinal stem cell populations in distinct niches. Science 334:1420-4
Singh, Manvendra K; Li, Yan; Li, Shanru et al. (2010) Gata4 and Gata5 cooperatively regulate cardiac myocyte proliferation in mice. J Biol Chem 285:1765-72
LeBoeuf, Matthew; Terrell, Anne; Trivedi, Sohum et al. (2010) Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Dev Cell 19:807-18
Trivedi, Chinmay M; Zhu, Wenting; Wang, Qiaohong et al. (2010) Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. Dev Cell 19:450-9

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