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）：刺猬信号在肺血管发育和重塑摘要中的作用：胚胎程序的概括表征了表现出异常细胞增殖的各种疾病。揭示胚胎血管发育的生物学复杂性具有更好地理解成年血管疾病（例如肺动脉高压（PAH））的发病机理。 PAH患者的血管室表现出异常的增殖能力，导致肺血管的适应不良重塑和血管腔的闭塞。正常静止的组织室中的异常增殖（例如肺脉管系统）通常会激活胚胎程序，这些程序在正常发育过程中驱动增殖和分化。 Sonic刺猬（SHH）是胚胎发育过程中组织组织相互作用和细胞命运的主要调节剂。有趣的是，还研究了刺猬信号传导，从纤维化到癌症等广泛的成人疾病，最终在最近批准的刺猬抑制剂治疗基础细胞癌患者中。然而，SHH在胚胎发育过程中驱动肺血管隔室的增殖和分化以及这可能与成年肺血管疾病有关的作用尚不清楚。在我的初步研究中，我证明SHH激活了发育过程中心源性中胚层内新型多胸腔祖先祖细胞（CPP）。这些CPP在克隆中产生肺脉管系统和心脏的多个隔室。 CPP中的刺猬信号的删除会导致肺血管发育不全，而血管平滑肌细胞（VSMC）分化损失。我还表明，刺猬信号继续激活成年肺脉管系统中的外在祖细胞，这些肺血管能够在PAH动物模型中扩散并分化为VSMC。这些数据表明，CPP和外在细胞分别是正常发育和异常血管重塑的VSMC祖细胞，两者都被刺猬信号传导激活。因此，我假设SHH在正常的肺血管发育和异常的血管重塑中起着潜在的平行作用，该重塑是通过在这两种临床环境中促进VSMC祖细胞增殖和分化。我将通过检查刺猬缺失在胚胎肺血管发育和PAH动物模型中的VSMC祖细胞中的刺猬缺失的影响来解决这一假设。该提案产生的机械理解可以为PAH患者的刺猬途径提供较强的理由。此外，该提案的成功完成将为我提供至关重要的培训，以成为肺血管生物学和疾病的独立研究者。