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: 8384685
• 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/8384685
• 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. PUBLIC HEALTH RELEVANCE: Our goal is to understand how the Wnt/PCP pathway regulates pulmonary angiogenesis and to demonstrate that mutations that disrupt pathway activation can result in PAH. Identification of novel genes could lead to novel therapies that could prevent progression and/or reverse established disease.

描述（由申请人提供）：这里提出的提案分为两部分：第一部分包含我提出的职业规划，第二部分描述了拟议项目的研究策略。我对血管生物学研究的兴趣始于我第一次临床接触特发性肺动脉高压（IPAH）患者。对这种疾病病理学的兴趣促使我继续在科罗拉多大学接受肺科医师培训，但由于家庭原因，在第一年的奖学金结束后，我从丹佛搬到了斯坦福大学，在血管研究领域的领军人物 Marlene Rabinovitch 博士的指导下继续我的研究培训。在过去的四年里，我 已经完成了两个项目，涉及肺动脉内皮 (PAEC) 和平滑肌细胞中 Wingless (Wnt) 和骨形态发生蛋白 (BMP) 信号传导之间的相互作用。此外，在同一时期，我还获得了 K12 和 Harold Amos 职业发展奖，以继续我目前作为一名医师科学家的职业生涯。自从最初提交以来，我已经成为斯坦福大学的医学助理教授，这个职位使我能够将 80% 的时间投入到与我的研究项目相关的活动中，例如参加科学会议、学习新的实验技术和数据分析方法以及向我的导师和同行展示我的研究进展报告。除了与我的导师 Rabinovitch 博士定期举行一对一会议外，我还将每季度与顾问和顾问小组会面，他们将提供批评和帮助 讨论与拟议研究相关的想法。为了及时了解最新的想法 在我的研究领域，我将参加斯坦福大学教师教授的一系列生物学、遗传学和生物统计学研究生课程，并学习负责任的研究行为的基本原则。最后，我剩余的时间 (20%) 将用于教学活动，旨在培训住院医师和研究员在住院和门诊环境中管理 PAH 患者。我的长期目标是拥有足够的已发表和初步数据来支持我作为研究人员的独立性，并提交 R01 资助，该资助将侧重于应用这些拟议研究中获得的数据来调查异常的 Wnt 信号传导如何促进 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，与肺压异常升高有关，如果不治疗，会导致充血性心力衰竭和过早死亡。 PAH 患者表现出远端小肺动脉进行性狭窄和丧失，而没有明显的代偿性血管再生，表明肺血管生成存在缺陷。我们小组和其他人最近的研究表明，骨形态发生蛋白受体（BMPR）II的突变可能通过减少肺动脉内皮细胞（PAEC）对损伤的存活和增殖而导致血管损失，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 之外，周细胞募集对于新形成血管的稳定也至关重要，但它们对 IPAH 发病机制的贡献尚未明确。我们最近表明，BMP 信号通过在 PAEC 中募集两条 Wnt 信号通路来促进肺血管生成：“经典”Wnt/β-连环蛋白 (? C) 和“非经典”Wnt/平面细胞极性 (PCP) 通路。根据我们的初步研究和文献综述，我们提出肺血管生成需要激活 Wnt/PCP 通路，方法是 1) 诱导 PAEC 组织成正确排列的血管，2) 促进周细胞募集到血管形成功能性血管。在使用从健康供体和 IPAH 患者肺部获得的 PAEC 和周细胞进行的一系列实验中，我们将证明 Wnt/PCP 信号传导是血管生成过程中指导 PAEC（目标 1）和周细胞（目标 2）行为所必需的，并且活性丧失与肺血管生成减少相关。此外，我们将通过对两种功能失调的 Wnt/PCP 信号转导动物模型的研究来补充这些细胞研究，这将有助于深入了解该途径与肺切除术后代偿性血管生成的生物学相关性（目标 3）。未来的研究将集中于减少 Wnt/PCP 信号传导的突变如何与 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 通路活性正常化的治疗干预措施如何通过恢复 IPAH 患者失去血管的再生能力来帮助预防进展并提高其生存率。 公共健康相关性：我们的目标是了解 Wnt/PCP 通路如何调节肺血管生成，并证明破坏通路激活的突变可能导致 PAH。新基因的鉴定可能会带来新的疗法，可以阻止进展和/或逆转已确定的疾病。