This proposal describes a comprehensive training program for the development of my investigative career in cardiovascular medicine. I have completed clinical training in Cardiovascular Disease at Brigham and Women's Hospital (BWH) and am deeply interested in understanding the molecular mechanisms of cardiac hypertrophy and failure. My immediate career goal is to immerse myself in a rigorous training program which is tailored to provide the experience, mentorship, and resources required for an eventual independent research career. My long-term career goal is to be an NIH-funded investigator in a tenure-track faculty position at academic medical center where I hope to contribute to the understanding of congestive heart failure. Currently, I am studying the transcriptional control of cardiac hypertrophy under the mentorship of Dr. Mukesh K. Jain, Director of the BWH Program in Transcriptional Cardiovascular Biology (PCTB). As detailed in this proposal, the research environment is ideal and my mentor is exemplary. The training will be enhanced by collaboration with Dr. Ronglih Liao and Dr. Jeffery Molkentin on studies of cardiac physiology and calcineurin signaling and by a highly structured career development plan that includes relevant coursework/symposia, conferences, and guidance from an expert advisory committee. I have made exciting preliminary observations which have led me to hypothesize that KLF15 is a novel negative regulator of cardiac hypertrophy that functions, in part, through inhibition of calcineurin-NFAT signaling in cardiomyocytes.
The Specific Aims of this project are: (1) To determine the role/regulation of KLF15 in cardiomyocyte gene expression/function in vitro under both basal and pro-hypertrophic conditions, (2) To determine the molecular basis by which KLF15 inhibits calcineurin-NFAT signaling in myocytes using broad-based molecular approaches, and (3) To determine the effect of KLF15 signaling on agonist and calcineurin-mediated cardiac hypertrophy in vivo using well-established mouse models of cardiac hypertrophy. We have generated KLF15(-/-) and transgenic animals for our in vivo work. Relevance: Heart failure is a serious condition that affects ~ 5 million people in the USA, and contributes to or causes ~ 300,000 deaths annually.
This research aims to understand the fundamental mechanisms of heart failure with the ultimate goal of finding new therapies to prevent / treat this devastating illness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL086614-04
Application #
7816943
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Roltsch, Mark
Project Start
2007-05-07
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$128,964
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Prosdocimo, Domenick A; Anand, Priti; Liao, Xudong et al. (2014) Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. J Biol Chem 289:5914-24
Anand, Priti; Brown, Jonathan D; Lin, Charles Y et al. (2013) BET bromodomains mediate transcriptional pause release in heart failure. Cell 154:569-82
Haldar, Saptarsi M; Stamler, Jonathan S (2013) S-nitrosylation: integrator of cardiovascular performance and oxygen delivery. J Clin Invest 123:101-10
Fujioka, Hisashi; Tandler, Bernard; Haldar, Saptarsi M et al. (2013) String mitochondria in mouse soleus muscle. Microsc Res Tech 76:237-41
Jeyaraj, Darwin; Haldar, Saptarsi M; Wan, Xiaoping et al. (2012) Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483:96-9
Haldar, Saptarsi M; Jeyaraj, Darwin; Anand, Priti et al. (2012) Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc Natl Acad Sci U S A 109:6739-44
Mahabeleshwar, Ganapati H; Kawanami, Daiji; Sharma, Nikunj et al. (2011) The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock. Immunity 34:715-28
Masuno, Kiriko; Haldar, Saptarsi M; Jeyaraj, Darwin et al. (2011) Expression profiling identifies Klf15 as a glucocorticoid target that regulates airway hyperresponsiveness. Am J Respir Cell Mol Biol 45:642-9
Lu, Yuan; Haldar, Saptarsi; Croce, Kevin et al. (2010) Kruppel-like factor 15 regulates smooth muscle response to vascular injury--brief report. Arterioscler Thromb Vasc Biol 30:1550-2
Haldar, Saptarsi M; Lu, Yuan; Jeyaraj, Darwin et al. (2010) Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation. Sci Transl Med 2:26ra26

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