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Robert D Lasley

Grant Detail

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Autophagy, Adenosine and Pyruvate Protection During Heart Surgery

1 June 1996 - 31 May 2013
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Total Funding: $ 6,034,648

FY 2011
5R01HL034579-25
$ 376,558
FY 2010
R01HL034579-24
$ 376,535
FY 2009
2R01HL034579-23A1
$ 388,887
FY 2008
5R01HL034579-22
$ 356,753
FY 2007
5R01HL034579-21
$ 356,753
FY 2006
7R01HL034579-20
$ 367,408
FY 2005
2R01HL034579-19A1
$ 365,958
FY 2003
5R01HL034579-18
$ 289,600
FY 2002
5R01HL034579-17
$ 289,600
FY 2001
5R01HL034579-16
$ 289,633
FY 2000
2R01HL034579-15
$ 290,000
FY 1998
5R01HL034579-14
$ 211,549
FY 1997
7R01HL034579-13
$ 204,687
FY 1996
5R01HL034579-12
$ 262,246
FY 1995
5R01HL034579-11
$ 161,972
FY 1995
3R01HL034579-11S1
$ 59,225
FY 1994
2R01HL034579-10
$ 221,270
FY 1993
5R01HL034579-09
$ 200,920
FY 1992
5R01HL034579-08
$ 192,549
FY 1991
7R01HL034579-07
$ 193,078
FY 1990
5R01HL034579-06
$ 195,164
FY 1989
2R01HL034579-05
$ 209,660
FY 1988
5R01HL034579-04
$ 51,435
FY 1986
7R01HL034579-03
$ 0
FY 1986
5R01HL034579-02
$ 60,168
FY 1985
1R01HL034579-01
$ 63,040
 
 
$ 6,034,648
Abstract

DESCRIPTION (provided by applicant): We have evidence that cardioprotective drugs and ischemic preconditioning stimulate autophagy and that inhibition of autophagy blocks cardioprotection. We suggest that autophagy is the final common pathway for many cardioprotective conditioning stimuli. We propose a novel hypothesis that autophagy is protective because it supports glutathione biosynthesis and/or amino acid transport across the autophagosomal membrane. Also, recognizing that an elevated NADH/NAD+ ratio results in ROS production from Complex I, and leads to mitochondrial damage and permeability transition pore opening, we hypothesize that interventions which shift the NADH/NAD+ ratio towards oxidation, such as pyruvate or Tat-Ndi1 administration, will decrease ROS production, preserve mitochondrial integrity, and decrease the oxidation of glutathione. Thus, we propose that a combination of agents that increase autophagy and modulate the NADH/NAD+ ratio will provide maximal cardioprotection. This combination will consist of an agent that briskly induces autophagosomal formation and an agent(s) that metabolically protects mitochondria. We will perform mechanistic studies using a rat heart Langendorff model of both stunning and necrosis. Translational studies will be evaluated in clinically relevant in situ myocardial stunning and infarction porcine preparations. We propose four specific aims: 1) Demonstrate that autophagy is necessary and sufficient for cardioprotection by conditioning agents in the rat Langendorff model using Tat-Atg5K130R. 2) Determine whether autophagy supports glutathione biosynthesis and/or proton pumping in pharmacologically conditioned rat hearts subjected to stunning and necrosis. 3) Modulate mitochondrial NADH levels to achieve cardioprotection using pyruvate or Tat-Ndi1 in rat hearts using stunning and necrosis models. 4) Optimize the upregulation of autophagy and maximize glutathione levels with preconditioning agents and pyruvate or Tat-Ndi1 to reduce myocardial stunning and infarct size in clinically relevant in situ porcine preparations. These studies will establish the fundamental mechanisms involved in autophagy and pharmacological conditioning and metabolic interventions. This knowledge will enable us to optimize cardioprotective protocols in humans. Public Health Relevance: Myocardial stunning and infarction are major short and long term causes of morbidity and mortality after percutaneous coronary interventions (PCI), reparative heart surgery, and heart transplantation. The objective of this project is to develop new therapies to increase the heart's tolerance to ischemia based on the process of autophagy. This will entail focusing on recent findings which implicate autophagy as a final common pathway for many pharmacological agents known to mimic the phenomenon of ischemic preconditioning.

47 Resulting Publications

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