The purpose of this Program Project Grant competitive renewal application entitled """"""""Discovery &Development of Therapeutic Genes for CHF"""""""" is to enable a number of scientists at VMRF and UCSD to maintain an efficient, interactive and mutually reinforcing program of basic and translational research to promote the discovery and development of therapeutic genes for congestive heart failure (CHF) and other cardiovascular diseases. The Program will facilitate the transition from discovery to clinical application of new therapeutic genes. This model combines discovery research with practical """"""""street-smart"""""""" preclinical development. Successfully attaining our goals will require separate but highly integrated Projects that contain the proper proportions f discovery research and focused preclinical development, an accomplished translational physiology Core, and an interactive group of VMRF and UCSD physician-scientists in an ideal environment. Our goals are to identify, perform mechanistic preclinical studies, and eventually to launch clinical trials of promising candidate genes. Strengths of our Program include: i) the breadth of our expertise across disciplines relevant to the goals of the NHLBI;2) the novelty of approaches ranging from bench science to translational studies using high-fidelity animal models of cardiovascular diseases;and 3) our previous success navigating the regulatory pathway from discovery to launching clinical gene therapy trials. Our Program, which is focused on fundamental mechanisms by which the failing heart can be treated (or heart failure avoided), includes three Projects: Project 1 (Dr. Hammond) will develop and test unique AC-related proteins as therapeutic agents for clinical CHF. Project 2 (Dr. Roth) will focus on the impact of cavelolin-3 and mitochondrial function in the pathophysiology and treatment of CHF;and Project 3 (Dr. Dillmann) will use gene transfer to attenuate adverse glycosylation of calcium-related proteins and resolve mitochondrial abnormalities in CHF. Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL066941-12
Application #
8743232
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
Mcdonald, Cheryl
Project Start
2000-09-29
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92161
Pandey, Amit K; Penny, William F; Bhargava, Valmik et al. (2016) Clinical Evaluation of Heart Failure: Agreement among Tests. PLoS One 11:e0161536
Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N Chin et al. (2016) One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance. JCI Insight 1:e88322
Schilling, Jan M; Horikawa, Yousuke T; Zemljic-Harpf, Alice E et al. (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28
Cividini, Federico; Scott, Brian T; Dai, Anzhi et al. (2016) O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts. J Biol Chem 291:26515-26528
See Hoe, Louise E; Schilling, Jan M; Busija, Anna R et al. (2016) Chronic β1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium. Eur J Pharmacol 789:1-7
Tran, Chinh; Stary, Creed M; Schilling, Jan M et al. (2015) Role of caveolin-3 in lymphocyte activation. Life Sci 121:35-9
Lai, N Chin; Gao, Mei Hua; Giamouridis, Dimosthenis et al. (2015) Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice. Hum Gene Ther 26:347-56
Schilling, Jan M; Roth, David M; Patel, Hemal H (2015) Caveolins in cardioprotection - translatability and mechanisms. Br J Pharmacol 172:2114-25
Sun, Junhui; Nguyen, Tiffany; Aponte, Angel M et al. (2015) Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc Res 106:227-36
Markandeya, Yogananda S; Phelan, Laura J; Woon, Marites T et al. (2015) Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes. J Biol Chem 290:22085-100

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