This proposal describes a 5-year training program for the development of an academic career in translational cardiovascular research. The candidate, having completed a clinical fellowship in Pediatric Critical Care Medicine, and a research fellowship at the Cardiovascular Research Institute (CVRI) at the University of California San Francisco (UCSF), is now poised to fully develop the scientific skill-set necessary to sustain an independent research program, utilizing the renowned, multidisciplinary environment offered by the CVRI and UCSF. The training program is designed to enable the candidate to apply integrated anatomic, physiologic, biochemical, cellular, and molecular investigations to addressing mechanisms of pulmonary vascular disease associated with congenital heart defects. The sponsor, Jeffrey R. Fineman, M.D., a Professor at UCSF and an internationally recognized expert in pulmonary vascular disease, has a strong history of successful mentorship. In addition, an advisory committee of distinguished medical scientists will provide additional scientific support and career guidance. Practical training in experimental techniques, design, and analysis Is combined with complementary didactic course-work. The proposed research plan seeks to elucidate the mechanisms underlying the development of pulmonary vascular disease secondary to increased pulmonary blood flow that is associated with several congenital heart defects. Previous work from Dr. Fineman's laboratory demonstrates that aberrant nitric oxide (NO) and endothelin-1 (ET-1) signaling contribute to this pathology. The candidate has subsequently generated preliminary data, which suggest a central role for PPARY in these interactions. Utilizing a unique clinically relevant ovine model of a congenital heart defect with increased pulmonary blood flow (created in utero by an aorto-pulmonary graft), and integrated biochemical, molecular, and cellular experiments, the proposal seeks to accomplish the following aims: (1) To determine alterations in endogenous PPARy expression under conditions of increased pulmonary blood flow, and the mechanisms and functional consequences of these alterations;and (2) To determine the physiologic, biochemical, cellular, and molecular alterations induced by PPARy agonist therapy under conditions of increased pulmonary blood flow. A role for PPARy in this pathology is novel. A better understanding of these interactions may have important implications for pulmonary as well as systemic vascular disorders. Relevance: Infants and children afflicted with congenital heart defects with increased pulmonary blood flow, suffer morbidity and mortality from the development of pulmonary vascular disease. Understanding the controlling mechanisms of this pathology might lead to novel and effective prevention and treatment strategies that will improve the survival and quality of life of this vulnerable population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL086513-04
Application #
7754457
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$121,770
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Radman, Monique; Keller, Roberta L; Oishi, Peter et al. (2014) Preoperative B-type natriuretic peptide levels are associated with outcome after total cavopulmonary connection (Fontan). J Thorac Cardiovasc Surg 148:212-9
Sharma, Shruti; Aramburo, Angela; Rafikov, Ruslan et al. (2013) L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. Pediatr Res 74:39-47
Oishi, Peter E; Cholsiripunlert, Sompob; Gong, Wenhui et al. (2011) Myo-mechanical analysis of isolated skeletal muscle. J Vis Exp :
Fratz, Sohrab; Fineman, Jeffrey R; Görlach, Agnes et al. (2011) Early determinants of pulmonary vascular remodeling in animal models of complex congenital heart disease. Circulation 123:916-23
Tian, Jing; Fratz, Sohrab; Hou, Yali et al. (2011) Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease. Physiol Genomics 43:87-98
Reel, Bhupinder; Oishi, Peter E; Hsu, Jong-Hau et al. (2009) Early elevations in B-type natriuretic peptide levels are associated with poor clinical outcomes in pediatric acute lung injury. Pediatr Pulmonol 44:1118-24
Oishi, Peter E; Wiseman, Dean A; Sharma, Shruti et al. (2008) Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow: a role for oxidative stress. Am J Physiol Lung Cell Mol Physiol 295:L756-66
Hsu, Jong-Hau; Oishi, Peter E; Keller, Roberta L et al. (2008) Perioperative B-type natriuretic peptide levels predict outcome after bidirectional cavopulmonary anastomosis and total cavopulmonary connection. J Thorac Cardiovasc Surg 135:746-53
Oishi, Peter; Sharma, Shruti; Grobe, Albert et al. (2007) Alterations in cGMP, soluble guanylate cyclase, phosphodiesterase 5, and B-type natriuretic peptide induced by chronic increased pulmonary blood flow in lambs. Pediatr Pulmonol 42:1057-71
Hsu, Jong-Hau; Keller, Roberta L; Chikovani, Omar et al. (2007) B-type natriuretic peptide levels predict outcome after neonatal cardiac surgery. J Thorac Cardiovasc Surg 134:939-45

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