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.

项目概要 这项 K08 提案将加快首席研究员实现成为一名 独立医师科学家致力于增加我们对致病机制的理解 肺动脉高压（PH）并开发创新疗法以改善结果。 候选人：Kel Vin Woo 博士是华盛顿大学医学院 (WUSM) 的医师兼科学家。 他完成了儿科心脏病学的研究金，并正在成纤维细胞交叉领域发展专业知识 世界权威David Ornitz博士指导下的生长因子（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 通过减轻内皮间质转化来降低缺氧诱导的 PH。他将利用所获得的技能 在他的研究期间，进一步分析血管平滑肌细胞中的 FGF 信号并使用腺病毒- 递送内皮 FGF 作为调节血管重塑的潜在方法。 职业发展计划：Woo 博士将在 Ornitz 博士的主要指导下从事这一领域的研究 以及 Curiel 博士（腺病毒载体学专家）的共同指导。此外，还有一支由校内和 校外顾问包括 PH、血管和肺生物学方面的专家，他们都拥有相当丰富的经验 培养独立调查人员的经验。 WUSM 提供了一个高度交互的环境 优良的设施、资源和机会。这个 5 年计划建立在 PI 之前的经验和进一步的基础上 丰富了他的训练，为他提供了独立所需的工具。它包括以下目标： (1) 掌握先进的小鼠血流动力学表型分析技术； (2) 熟练掌握腺病毒 使用缺氧诱导的血管重塑的临床前模型来改善 PH 结果； (3) 在不同场所传播研究成果并积极建立富有成效的合作。 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 平滑肌细胞可防止缺氧引起的 PH 值。具体目标 1 将研究平滑肌如何 细胞 FGF 可防止肺血管重塑。目标 2 将探究内皮细胞如何靶向腺病毒 - 递送的 FGF 可减少缺氧引起的血管重塑和 PH 严重程度。完成提议后 研究中，Woo 博士将精通：(1) 调节对内皮细胞和平滑肌细胞重要的细胞内通路 肌肉细胞重塑； (2) 分析新开发的条件敲除小鼠以确定血流动力学 对肺部的影响； (3) 开发将基因传递至肺内皮的方法作为潜在的治疗方法 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疾病 血管疾病和血管重塑中的内皮-平滑肌相互作用。完成后 拟议的培训，吴博士将获得成为独立调查员所需的专业知识 致力于减轻肺部疾病的负担，与 NHLBI 的使命保持一致。