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

• 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
• 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

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.

项目摘要 该K08提案将加快主要研究人员的进步，以成为他成为一个目标的目标 独立的身体科学家专注于提高我们对病原机制的理解 肺动脉高压（pH）和开发创新疗法以改善预后。 候选人：Kel Vin Woo博士是华盛顿大学医学院（WUSM）的身体科学家。 他完成了小儿心脏病学研究金，并正在成纤维细胞的交集发展专业知识 在世界权威大卫·奥尼茨（David Ornitz）的心态下，增长因素（FGF）信号传导和血管生物学 关于FGF生物学。在Ornitz博士的指导下，PI研究了内皮FGF信号如何调节 通过减轻内皮到间质转变，缺氧引起的pH值。他将利用获得的技能 在他的团契期间，以进一步分析血管平滑肌细胞中的FGF信号传导，并使用腺病毒 - 将内皮FGF作为调节血管重塑的潜在方法。 职业发展计划：Woo博士将通过Ornitz博士的主要精神训练进行这项研究。 以及Curiel博士（腺病毒载体学专家）的授权。此外，室内和 外壁外顾问包括pH和血管和肺部生物学专家，都考虑了 有培养独立研究人员的经验。 WUSM提供了一个高度互动的环境 优秀的设施，资源和机会。这个五年计划是基于PI先前的经验，进一步的 丰富他的培训，为他提供独立所需的工具。它包括以下对象： （1）高级小鼠血液动力学表型中的主技术； （2）精通腺病毒 使用缺氧引起的血管重塑的临床前模型改善pH结果的工程； （3） 在潜水员场所传播研究结果，并积极建立产品合作。 研究计划：该提案的总体假设是肺内皮和血管中的FGF信号传导 平滑肌细胞可预防缺氧引起的pH值。特定的目标1将研究平滑肌肉 细胞FGF防止肺血管重塑。 AIM 2将询问内皮靶向腺病毒的如何 递送的FGF减少了缺氧引起的血管重塑和pH严重程度。提议完成后 研究，Woo博士将精通：（1）调节对内皮和光滑重要的细胞内途径 肌肉细胞重塑； （2）分析了新开发的条件敲除小鼠以确定血液动力学 对肺的影响； （3）开发基因递送至肺内皮的方法作为一种潜在的疗法 用于肺血管疾病。这些获得的技能将很容易适用于其他形式的肺部 血管重塑中的血管疾病和内皮平滑肌肉相互作用。完成后 拟议的培训，Woo博士将获得必要的专业知识，成为一名独立研究者 专注于减少与NHLBI任务保持一致的肺部疾病伯恩。