A 5-year research program is proposed to enhance an academic career in Pediatric Cardiology. The principal investigator has completed a residency in Pediatrics and a fellowship in Pediatric Cardiology. This career development plan will add depth to his scientific skills in the field of myocardial regeneration and heart failure. Two internationally renowned faculty members, David Clapham and Mark Keating, will sponsor the applicant. An advisory committee consisting of three leading scientists in their fields will provide the applicant with research and career advice. Humans do not regenerate their hearts. Instead, the human heart responds to injury with scar formation, not with proliferation, the cellular basis of regeneration. This inability to regenerate contributes significantly to cardiovascular morbidity and mortality. By contrast, lower vertebrates, e.g. newt and zebrafish, can regenerate their hearts by cardiomyocyte proliferation. Adult mammalian cardiomyocytes are believed to be quiescent, i.e. they do not proliferate. However, recent work in the Keating laboratory suggests that mammalian cardiomyocytes retain the latent potential to proliferate. The PI focused on the identification of factors that release the proliferative potential of mammalian cardiomyocytes. Preliminary data indicate that periostin, a component of the extracellular matrix, stimulates cardiomyocyte proliferation. Periostin is absent from normal myocardium, but expressed in the injured heart. Our data support the hypothesis that periostin has a beneficial function in myocardial recovery.
The specific aims are: 1. Characterize the cellular effects of periostin in vitro: We will study the effect of periostin on cardiomyocyte cell cycle progression, proliferation, and survival in cultured primary rat cardiomyocytes. 2. Characterize the molecular function of periostin in vitro: We will characterize the receptor and the intracellular signaling pathways activated by periostin in cardiomyocytes. 3. Characterize the function of periostin in the heart in vivo: We will express periostin in the normal rat heart using adenoviral gene transfer. We will also pharmacologically disrupt the periostin action in rats with myocardial injury. We will evaluate the cardiac function with echocardiography and catheterization, and determine the tissue response with immunofluorescence microscopy. These studies will provide the first detailed functional analysis of periostin in the recovery of the injured mammalian myocardium. The long-term goal is to provide new therapeutic approaches to heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL085143-04
Application #
8293229
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Carlson, Drew E
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$129,060
Indirect Cost
$9,560
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhang, Cheng-Hai; Kühn, Bernhard (2014) Muscling up the heart: a preadolescent cardiomyocyte proliferation contributes to heart growth. Circ Res 115:690-2
Parodi, Emily M; Kuhn, Bernhard (2014) Signalling between microvascular endothelium and cardiomyocytes through neuregulin. Cardiovasc Res 102:194-204
Senyo, Samuel E; Lee, Richard T; Kühn, Bernhard (2014) Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res 13:532-41
Khaladkar, Mugdha; Buckley, Peter T; Lee, Miler T et al. (2013) Subcellular RNA sequencing reveals broad presence of cytoplasmic intron-sequence retaining transcripts in mouse and rat neurons. PLoS One 8:e76194
Mollova, Mariya; Bersell, Kevin; Walsh, Stuart et al. (2013) Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A 110:1446-51
Bersell, Kevin; Choudhury, Sangita; Mollova, Mariya et al. (2013) Moderate and high amounts of tamoxifen in *MHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death. Dis Model Mech 6:1459-69
Kuhn, Bernhard (2013) ERBB2 inhibition and heart failure. N Engl J Med 368:875-6
Wadugu, Brian; Kuhn, Bernhard (2012) The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation. Am J Physiol Heart Circ Physiol 302:H2139-47