The role of the Wnt/planar cell polarity pathway in pulmonary angiogenesis

Wnt/平面细胞极性通路在肺血管生成中的作用

• 批准号: 8688333
• 负责人: VINICIO A DE JESUS PEREZ
• 金额: $ 13.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688333
• 关键词: Animal Model; Award; Behavior; Biological; Biology; Biometry; Blood Vessels; Bone Morphogenetic Proteins; Cell Communication; Cell Culture Techniques; Cell Polarity; Cell Survival; Cells; Cessation of life; Clinical; Colorado; Complement; Congestive Heart Failure; Data; Data Analyses; Defect; Development; Disease; Disease Progression; Distal; Educational process of instructing; Endocytosis; Enrollment; Faculty; Family; Fellowship; Future; Genes; Genetic; Genetic Determinism; Goals; Grant; Impairment; Injury; Inpatients; K-Series Research Career Programs; Lead; Learning; Left; Link; Lung; Mediating; Medicine; Mentors; Mentorship; Methods; Morphogenesis; Mus; Mutation; Natural regeneration; Outpatients; Pathogenesis; Pathway interactions; Patients; Pericytes; Physicians; Pneumonectomy; Positioning Attribute; Progress Reports; Proteins; Publishing; Pulmonary Hypertension; Pulmonary artery structure; Research; Research Personnel; Research Project Grants; Research Training; Review Literature; Role; SECTM1 gene; Scientist; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Study models; Techniques; Therapeutic Intervention; Time; Tissues; Training; Transgenic Mice; Tube; Universities; Work; angiogenesis; base; bone morphogenetic protein receptor type II; career; cell motility; cell type; gain of function; improved; insight; interest; meetings; mouse model; mutant; novel; novel strategies; overexpression; peer; premature; pressure; prevent; professor; pulmonary arterial hypertension; pulmonary artery endothelial cell; receptor; research study; response; response to injury; symposium

DESCRIPTION (provided by applicant): The proposal presented here is divided into two parts: the first contains my proposed career plan and the second describes the research strategy for the proposed project. My interest in vascular biology research began with my first clinical encounters with patients suffering from idiopathic pulmonary hypertension (IPAH). Interest in the pathobiology of the disease led me to continue training as a pulmonologist at the University of Colorado but, due to family related reasons, I moved from Denver to Stanford University after my first year of fellowship to continue my research training under the mentorship of Dr. Marlene Rabinovitch, a leader in the field of vascular research. Over the last four years, I have completed two projects dealing with the interaction between Wingless (Wnt) and bone morphogenetic protein (BMP) signaling in pulmonary artery endothelial (PAEC) and smooth muscle cells. Furthermore, during the same time period, I have been awarded both a K12 and, a Harold Amos career development award to continue my current career track as a physician scientist. Since the initial submission, I have become an assistant professor of medicine at Stanford University, a position that allows me to devote 80% of my time to activities related to my research project such as participating in scientific conferences, learning new experimental techniques and methods of data analysis and presenting progress reports of my research to my advisors and peers. In addition to regular one-on-one meetings with my mentor Dr. Rabinovitch, I will meet quarterly with a panel of advisors and consultants that will provide criticism and help discuss ideas related to the proposed research. In an effort to keep abreast of the latest ideas in my field of research, I will enroll in a series of graduate courses in biology, genetics and biostatistics taught by Stanford University faculty and learn the basic principles for responsible conduct in research. Finally, the remainder of my time (20%) will be spent in teaching activities aimed at training residents and fellows in the management of PAH patients in both inpatient and outpatient settings. My long term goals are to have sufficient published and preliminary data to support my independence as an investigator and to submit an R01 grant that will focus on applying the data obtained in these proposed studies to investigating how abnormal Wnt signaling may contribute to IPAH development. The second part of the proposal contains the research plan. IPAH is a rare and progressive disorder associated with abnormally elevated pulmonary pressures that, if untreated, lead to congestive heart failure and premature death. Patients with PAH demonstrate progressive narrowing and loss of small distal pulmonary arteries without significant compensatory vascular regeneration indicating that a defect in pulmonary angiogenesis is present. Recent studies by our group and others have shown that mutations in the bone morphogenetic protein receptor (BMPR) II could contribute to vessel loss by reducing pulmonary artery endothelial cell (PAEC) survival and proliferation in response to injury but the mechanisms by which BMPRI can regulate these angiogenic responses have not been well characterized. In addition to PAECs, pericyte recruitment is critical for stabilization o newly formed vessels but their contribution to the pathogenesis of IPAH has not been well established. We have recently shown that BMP signaling promotes pulmonary angiogenesis by recruitment of two Wnt signaling pathways in PAECs: the "canonical" Wnt/?-catenin (? C) and the "non-canonical" Wnt/planar cell polarity (PCP) pathways. Based on our preliminary studies and our review of the literature, we propose that activation of the Wnt/PCP pathway is required for pulmonary angiogenesis by 1) inducing PAEC to organize into properly aligned vascular tubes and 2) by promoting pericyte recruitment to vascular tubes to form functional blood vessels. In a series of experiments using PAECs and pericytes obtained from the lungs of healthy donors and IPAH patients, we will demonstrate that Wnt/PCP signaling is required to direct PAEC (Aim 1) and pericyte (Aim 2) behavior during angiogenesis and that loss of activity correlates with reduced pulmonary angiogenesis. Furthermore, we will complement these cell studies with work on two animal models of dysfunctional Wnt/PCP signaling that will help provide insight into the biological relevance of this pathway to compensatory angiogenesis following pneumonectomy (Aim 3). Future studies will center on how mutations that reduce Wnt/PCP signaling can genetically interact with BMPRII mutations to promote development of IPAH and how therapeutic interventions aimed at normalizing Wnt/PCP pathway activity in PAEC and pericytes could help prevent progression and improve survival in IPAH patients by restoring their ability to regenerate lost vessels.

描述(由申请人提供)：这里提出的建议分为两部分：第一部分包括我提出的职业生涯计划，第二部分描述了建议项目的研究策略。我对血管生物学研究的兴趣始于我第一次与患有特发性肺动脉高压(IPAH)的患者进行临床接触。对这种疾病的病理生物学的兴趣促使我继续在科罗拉多大学接受肺科医生的培训，但由于与家庭相关的原因，在获得第一年奖学金后，我从丹佛搬到斯坦福大学，在血管研究领域的领军人物玛琳·拉比诺维奇博士的指导下继续我的研究培训。在过去四年里，我 已经完成了两个项目，涉及无翼(Wnt)和骨形态发生蛋白(BMP)信号在肺动脉内皮细胞(PAEC)和平滑肌细胞中的相互作用。此外，在同一时期，我还获得了K12和哈罗德·阿莫斯职业发展奖，以继续我目前作为内科科学家的职业生涯。自从最初提交以来，我已经成为斯坦福大学的一名医学助理教授，这个职位允许我将80%的时间投入到与我的研究项目相关的活动中，比如参加科学会议，学习新的实验技术和数据分析方法，以及向我的导师和同事展示我的研究进展报告。除了定期与我的导师拉比诺维奇博士进行一对一的会面外，我还将每季度与一个顾问小组会面，他们将提供批评和帮助 讨论与拟议研究相关的想法。为了跟上最新的思想 在我的研究领域，我将参加斯坦福大学教员教授的一系列生物学、遗传学和生物统计学的研究生课程，并学习负责任的研究行为的基本原则。最后，我剩下的时间(20%)将花在教学活动上，旨在培训住院医生和研究员在住院和门诊环境下管理PAH患者。我的长期目标是有足够的已发表的和初步的数据来支持我作为一名研究人员的独立性，并提交一份R01拨款，重点是应用在这些拟议研究中获得的数据来调查异常的Wnt信号如何有助于IPAH的发展。提案的第二部分包含研究计划。IPAH是一种罕见的进行性疾病，与异常升高的肺压有关，如果不治疗，会导致充血性心力衰竭和过早死亡。PAH患者表现为肺远端小动脉进行性狭窄和丢失，但无明显的代偿性血管再生，提示存在肺血管生成缺陷。我们等人最近的研究表明，骨形态发生蛋白受体(BMPR)II的突变可能通过减少损伤后肺动脉内皮细胞(PAEC)的存活和增殖而导致血管丢失，但BMPRI调节这些血管生成反应的机制尚未得到很好的表征。除了PAEC外，周细胞募集对于稳定新生血管至关重要，但它们在IPAH发病机制中的作用尚未得到很好的证实。我们最近发现，BMP信号通过在肺内皮细胞中募集两条Wnt信号通路促进肺血管生成：“典型的”Wnt/？-catenin(？)C)和“非正则”Wnt/平面细胞极性(PCP)通路。根据我们的初步研究和文献回顾，我们认为Wnt/PCP通路的激活是肺血管生成所必需的，1)诱导PAEC组织成正确排列的血管管，2)促进周细胞募集到血管管形成功能性血管。在一系列使用健康供者和IPAH患者肺组织的PAEC和周细胞的实验中，我们将证明WNT/PCP信号在血管生成过程中需要指导PAEC(AIM 1)和周细胞(AIM 2)的行为，并且活性的丧失与肺血管生成的减少相关。此外，我们将通过两个Wnt/PCP信号失灵的动物模型来补充这些细胞研究，这将有助于深入了解这一途径与肺切除后代偿性血管生成的生物学相关性(目标3)。未来的研究将集中在减少Wnt/PCP信号的突变如何与BMPRII突变在基因上相互作用以促进IPAH的发展，以及旨在使PAEC和周细胞中Wnt/PCP途径活性正常化的治疗干预如何通过恢复IPAH患者再生丢失血管的能力来帮助防止进展和提高生存率。