Heart failure remains a leading cause of hospital admissions and mortality in the elderly and current interventional approaches often fail to treat the underlying cause of pathogenesis. Preservation of structure and function in the aging myocardium is most likely to be successful via ongoing cellular repair and replacement as well as enhanced survival of existing cardiomyocytes that generate contractile force. The long term goal of the study is to promote myocardial structure and function in the aging heart. The short term goal of this proposal is to enhance survival of cardiomyocytes and their precursor cells to render the heart resistant to effects of aging and pathological insults. The hypothesis of this proposal asserts that nuclear translocation of activated Akt promotes survival of cardiomyocytes and stem cell precursors to enhance myocardial viability and resist deterioration of cardiac structure and function from aging. Specifically, experiments are designed to understand the molecular and biological effects of targeting Akt kinase expression to the nucleus of cardiomyocytes and their progenitor cell population.
Specific aims of the proposal will demonstrate that: 1) Akt activity and nuclear translocation in cardiac stem cells are diminished with advancing age; 2) Nuclear-targeted Akt (Akt-nuc) activity increases cardiomyocyte proliferation, promotes survival, and antagonizes senescence in vitro; 3) Akt-nuc activity increases cardiomyocyte stem cell proliferation, promotes survival, and antagonizes senescence in vivo; and 4) myocardial-specific expression of Akt-nuc enhances hemodynamic function of the aging heart. Cardiomyocytes and their precursor cells will be characterized in genetically engineered transgenic mouse lines as well as recombinant viral vectors that express or activate Akt-nuc. Innovative combinations of in vitro and in vivo experiments are proposed utilizing molecular, biochemical, microscopic, and transgenic approaches to assess mechanisms that enhance stem cell survival and retard myocardial aging. The significance of these results will be to characterize a critical molecular regulatory pathway for cardiomyocyte progenitor survival that antagonizes cardiac senescence. Furthermore, significant implications exist for treatment of the aging myocardium as future interventional approaches will capitalize upon the use cardiac stem cells as therapeutic reagents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG023071-03
Application #
7260434
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$323,123
Indirect Cost
Name
New York Medical College
Department
Type
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Signore, Sergio; Sorrentino, Andrea; Borghetti, Giulia et al. (2015) Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy. Nat Commun 6:8803
Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46
Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna et al. (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41-55
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article ""Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes"". Circulation 129:e510-1
Anversa, Piero; Leri, Annarosa (2013) Innate regeneration in the aging heart: healing from within. Mayo Clin Proc 88:871-83
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2013) Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation 128:1286-97
Goichberg, Polina; Kannappan, Ramaswamy; Cimini, Maria et al. (2013) Age-associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128:2211-23
Anversa, Piero; Leri, Annarosa; Kajstura, Jan (2012) Biased DNA segregation during stem cell division. Circ Res 110:1403-7
Leri, Annarosa; Kajstura, Jan (2012) Created equal? The many facets of cell reprogramming. Circ Res 111:152-5
Kajstura, Jan; Bai, Yingnan; Cappetta, Donato et al. (2012) Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium. Circ Res 111:894-906

Showing the most recent 10 out of 61 publications