The roles of Hedgehog signaling in pulmonary vascular development and remodeling

Hedgehog信号在肺血管发育和重塑中的作用

基本信息

批准号：
8766755
负责人：
Tien Peng
金额：
$ 13.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8766755
关键词：
Address Adult Animal Model Apoptosis Automobile Driving Basal cell carcinoma Biological Biology Blood Vessels Cardiac Cardiac Myocytes Cardiopulmonary Cell Communication Cell Differentiation process Cell Proliferation Cessation of life Clinical Data Development Disease Drug Targeting Embryo Embryonic Development Erinaceidae Exhibits Fibrosis Genetic Programming Heart Heart failure Hypertension In Vitro Lung Lung diseases Malignant Neoplasms Mesoderm Pathogenesis Pathologic Pathway interactions Patients Pericytes Play Population Proliferating Research Personnel Role Smooth Muscle Smooth Muscle Myocytes Testing Tissues Training Vascular Diseases Vascular Smooth Muscle Vascular remodeling Ventricular embryonic stem cell hemodynamics in vivo inhibitor/antagonist insight novel progenitor programs public health relevance pulmonary arterial hypertension smoothened signaling pathway therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The role of Hedgehog signaling in pulmonary vascular development and remodeling ABSTRACT: The recapitulation of embryonic programs characterizes a variety of diseases that manifest abnormal cellular proliferation. Unraveling the biological complexity of embryonic vascular development has the potential to provide better understanding of the pathogenesis of adult vascular diseases such as pulmonary arterial hypertension (PAH). Vascular compartments in patients with PAH exhibit abnormal proliferative capacity that causes maladaptive remodeling of the pulmonary vasculature and obliteration of the vascular lumen. Aberrant proliferation in normally quiescent tissue compartments such as the pulmonary vasculature often reactivates embryonic programs that drive proliferation and differentiation during normal development. Sonic Hedgehog (Shh) is a master regulator of tissue-tissue interaction and cell fate during embryonic development. Interestingly, Hedgehog signaling has also been studied in a wide range of adult diseases ranging from fibrosis to cancer, culminating in the recent approval of a Hedgehog inhibitor to treat patients with basal cell carcinoma. However, the role of Shh in driving the proliferation and differentiation of pulmonary vascular compartments during embryonic development, and how this might relate to adult pulmonary vascular disease is less clear. In my preliminary studies, I demonstrated that Shh activates a novel population of multipotent cardiopulmonary progenitors (CPPs) within the cardiogenic mesoderm during development. These CPPs clonally generate multiple compartments of the pulmonary vasculature and the heart. Deletion of Hedgehog signaling within CPPs causes pulmonary vascular hypoplasia with loss of vascular smooth muscle cell (VSMC) differentiation. I also showed that Hedgehog signaling continues to activate adventitial progenitors in the adult pulmonary vasculature that are capable of proliferating and differentiating into VSMCs in an animal model of PAH. These data suggest that CPPs and adventitial cells are VSMC progenitors in normal development and abnormal vascular remodeling respectively, with both activated by Hedgehog signaling. Therefore, I hypothesize that Shh plays potentially parallel roles in normal pulmonary vascular development and abnormal vascular remodeling by promoting VSMC progenitor proliferation and differentiation in both clinical contexts. I will address this hypothesis by examining the effect of Hedgehog deletion in VSMC progenitors in both embryonic pulmonary vascular development and in an animal model of PAH. Mechanistic understanding generated from this proposal could provide a strong rationale for therapeutic targeting of the Hedgehog pathway in patients with PAH. Furthermore, successful completion of this proposal would provide me with the crucial training to become an independent investigator in pulmonary vascular biology and disease.

描述（由申请人提供）：Hedgehog 信号传导在肺血管发育和重塑中的作用摘要：胚胎程序的重演表征了多种表现出异常细胞增殖的疾病。揭示胚胎血管发育的生物学复杂性有可能更好地了解肺动脉高压（PAH）等成人血管疾病的发病机制。 PAH 患者的血管室表现出异常的增殖能力，导致肺血管系统的适应不良重塑和血管腔闭塞。通常静止的组织区室（例如肺脉管系统）中的异常增殖通常会重新激活在正常发育过程中驱动增殖和分化的胚胎程序。 Sonic Hedgehog (Shh) 是胚胎发育过程中组织与组织相互作用和细胞命运的主要调节者。有趣的是，Hedgehog 信号传导也在从纤维化到癌症等多种成人疾病中进行了研究，最终导致最近批准了一种 Hedgehog 抑制剂来治疗基底细胞癌患者。然而，Shh 在胚胎发育过程中驱动肺血管室增殖和分化的作用以及这与成人肺血管疾病的关系尚不清楚。在我的初步研究中，我证明了Shh在发育过程中激活了心源性中胚层内的一群新的多能心肺祖细胞（CPP）。这些 CPP 克隆产生肺血管系统和心脏的多个区室。 CPP 内 Hedgehog 信号传导的缺失会导致肺血管发育不全，并导致血管平滑肌细胞 (VSMC) 分化丧失。我还表明，Hedgehog 信号传导持续激活成人肺血管系统中的外膜祖细胞，这些祖细胞能够在 PAH 动物模型中增殖并分化为 VSMC。这些数据表明，CPP 和外膜细胞分别是正常发育和异常血管重塑中的 VSMC 祖细胞，两者均由 Hedgehog 信号传导激活。因此，我推测Shh通过促进两种临床情况下的VSMC祖细胞增殖和分化，在正常肺血管发育和异常血管重塑中发挥潜在的平行作用。我将通过检查 VSMC 祖细胞中 Hedgehog 缺失对胚胎肺血管发育和 PAH 动物模型的影响来解决这一假设。该提议产生的机制理解可以为 PAH 患者的 Hedgehog 通路靶向治疗提供强有力的理论依据。此外，成功完成该提案将为我提供重要的培训，使我成为肺血管生物学和疾病的独立研究者。