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The protective role of fibroblast growth factor signaling in hypoxia-induced pulmonary hypertension

成纤维细胞生长因子信号传导在缺氧诱导的肺动脉高压中的保护作用

基本信息

批准号：
10506740
负责人：
Kel Vin WOO
金额：
$ 16.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506740
关键词：
Adenovirus Vector Adenoviruses Adult Affect Biology Blood Vessels Bronchopulmonary Dysplasia Cardiopulmonary Cell Communication Cells Cessation of life Chronic Obstructive Pulmonary Disease Classification Collaborations Data Development Development Plans Disease Disease model Distal Endothelial Cells Endothelium Engineering Exposure to Extramural Activities FGFR1 gene Fellowship Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene Delivery Genetic Genetic Models Goals Hypoxemia Hypoxia Innovative Therapy Knockout Mice Knowledge Laboratories Ligands Lung Lung diseases Mentorship Mesenchymal Methods Mission Modeling Molecular Morbidity - disease rate Mus Muscle National Heart, Lung, and Blood Institute Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pediatric cardiology Phenotype Physicians Physiological Pre-Clinical Model Premature Infant Principal Investigator Production Pulmonary Hypertension Pulmonary artery structure Regulation Research Research Personnel Resources Role Scientist Severities Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stress Structure of parenchyma of lung Techniques Therapeutic Therapeutic Intervention Training Training Programs Transforming Growth Factor beta United States National Institutes of Health Universities Vascular Endothelial Cell Vascular Endothelium Vascular Smooth Muscle Vascular remodeling Washington Work adenovirus mediated delivery angiogenesis authority career development collaborative environment conditional knockout early detection biomarkers experience gain of function gene therapy hemodynamics hypoxia-induced pulmonary hypertension improved improved outcome in vivo loss of function medical schools mortality mouse genetics new therapeutic target premature prevent pulmonary vascular disorder pulmonary vascular remodeling response skills therapeutic target tissue injury tool translational approach

项目摘要

Project Summary This K08 proposal will expedite the principal investigator’s progress towards his goal of becoming an independent physician-scientist focused on increasing our understanding of pathogenic mechanisms of pulmonary hypertension (PH) and developing innovative therapies to improve outcomes. Candidate: Dr. Kel Vin Woo is a physician-scientist at Washington University School of Medicine (WUSM). He completed a fellowship in Pediatric Cardiology and is developing expertise at the intersection of Fibroblast Growth Factors (FGF) signaling and vascular biology under the mentorship of Dr. David Ornitz, a world authority on FGF biology. Under Dr. Ornitz’s mentorship, the PI investigated how endothelial FGF signaling modulates hypoxia-induced PH by mitigating endothelial-to-mesenchymal transition. He will leverage the skills gained during his fellowship to further analyze FGF signaling in vascular smooth muscle cells and use adenovirus- delivered endothelial FGF as a potential method of regulating vascular remodeling. Career Development Plan: Dr. Woo will pursue this line of research with primary mentorship from Dr. Ornitz and co-mentorship from Dr. Curiel (an expert in adenovirus vectorology). Additionally, a team of intramural and extramural advisors include experts in PH, and vascular and pulmonary biology, and all have considerable experience in nurturing independent investigators. WUSM provides a highly interactive environment with excellent facilities, resources and opportunities. This 5-year plan builds on the PI’s prior experience and further enriches his training, providing him with the tools needed for independence. It includes the following objectives: (1) Master techniques in advanced mouse hemodynamic phenotyping; (2) Become proficient with adenovirus engineering to improve PH outcomes using preclinical models of hypoxia-induced vascular remodeling; (3) Disseminate research findings in diverse venues and actively establish productive collaborations. Research Plan: The overall hypothesis of the proposal is that FGF signaling in lung endothelial and vascular smooth muscle cells protects against hypoxia-induced PH. Specific Aim 1 will investigate how smooth muscle cell FGF prevents pulmonary vascular remodeling. Aim 2 will interrogate how endothelial targeted adenovirus- delivered FGF reduces hypoxia-induced vascular remodeling and PH severity. Upon completion of the proposed research, Dr. Woo will be proficient in: (1) modulating intracellular pathways important for endothelial and smooth muscle cell remodeling; (2) analyzing newly developed conditional knockout mice to ascertain the hemodynamic effects on the lungs; and (3) developing approaches for gene delivery to lung endothelium as a potential therapy for pulmonary vascular disease. These acquired skills will be readily applicable to other forms pulmonary vascular disease and endothelial-smooth muscle interactions in vascular remodeling. Upon completion of the proposed training, Dr. Woo will have acquired the necessary expertise to become an independent investigator focused on reducing the burden of pulmonary diseases, in alignment with the NHLBI mission.

项目总结