This is a revised (A1) competitive renewal application for an R01 initially focused on the role of a novel homeodomain protein called Hop that we discovered in the embryonic heart. We have found that Hop loss of function results in a developmental cardiac defect and that over-expression results in cardiac hypertrophy. Hop can function at the molecular level as a transcriptional co-repressor by recruiting class I HDACs. This finding led us to test the effects of HDAC inhibitors and we have found that these agents can block cardiac hypertrophy induced by Hop over-expression and also hypertrophy resulting from other stresses including beta-adrenergic agonists and stretch. Therefore, we have sought the specific class I HDAC(s) that account for these effects, and we have identified high levels of HDAC2 in the developing and adult heart. HDAC2 loss of function results in mice that are resistant to Hop- induced cardiac hypertrophy and to hypertrophy induced by beta-adrenergic agonists. We have shown that resistance to hypertrophy in these models is caused by constitutive activation of GSK3-beta, since antagonists of GSK3-beta restore the ability to hypertrophy on HDAC2 null animals. Our data indicates that HDAC2 affects the AKT-GSK3-beta pathway by directly repressing a novel inositol polyphosphate phosphatase called INPP5F, which functions to degrade PIP3 and thus affects the AKT cascade. These findings have direct clinical and translational implications since phosphatases are excellent drugable targets for the treatment of cardiovascular disease and because HDAC inhibitors are already in clinical trials for the treatment of cancer and could be readily adapted for use in the cardiac arena. Therefore, we will pursue these observations by: 1) Developing a floxed allele of HDAC2 in order to perform tissue and temporal specific deletion and to determine the effects of HDAC2 loss of function on regression of pre-established hypertrophy;2) Elucidation of the genetic and biochemical interaction between Hop and HDAC2, and;3) Examination of the function of INPP5F through gain and loss of function approaches in cells and in mice. These experiments offer strong prospects for developing new therapeutic avenues and paradigms for the treatment of cardiac hypertrophy and heart failure, with implications for the more general fields of cellular and organ growth regulation.

Public Health Relevance

This project focuses on the causes of congestive heart failure, and on finding new therapeutic targets. Heart failure is a leading cause of death and disability in the United States, and the incidence is rising. We have found that HDAC inhibitors, which are drugs currently in clinical trials for cancer therapy, have beneficial effects in terms of heart failure prevention in animal models. This project explores the possibility that an enzyme called HDAC2, expressed in the heart, is the molecular target for HDAC inhibitors, and that it functions by regulating a novel phosphatase in the heart called INPP5F. We hope to determine if HDAC2 and INPP5F represent new targets for the development of specific therapies for heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071546-09
Application #
8242726
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2003-09-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$389,813
Indirect Cost
$142,313
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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 166:451-67
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
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
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
Li, Deqiang; Takeda, Norifumi; Jain, Rajan et al. (2015) Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res 15:522-9
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
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

Showing the most recent 10 out of 27 publications