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

• 批准号: 9300965
• 负责人: Tien Peng
• 金额: $ 16.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/9300965
• 关键词: Address; Adult; Animal Model; Apoptosis; Automobile Driving; Basal cell carcinoma; Biological; Biology; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Clinical; Data; Development; Disease; Drug Targeting; Embryo; Embryonic Development; Erinaceidae; Exhibits; Fibrosis; Genetic; Genetic Transcription; Heart; Heart failure; Hypertension; In Vitro; Lung; Lung diseases; Malignant Neoplasms; Mesoderm; Muscle Cells; Pathogenesis; Pathologic; Pathway interactions; Patients; Pericytes; Pharmacology; Play; Population; Proliferating; Research Personnel; Role; SHH gene; Smooth Muscle; Stem cells; 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; vascular abnormality

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信号在肺血管发育和重塑中的作用摘要：胚胎程序的概括描述了各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成人血管疾病的发病机制，如肺动脉高压(PAH)。PAH患者的血管间隔表现出异常的增殖能力，导致肺血管系统的不适应性重塑和血管腔的闭塞。在正常发育过程中，正常静止的组织隔室(如肺血管)中的异常增殖通常会重新激活胚胎程序，从而推动增殖和分化。Sonic Hedgehog(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者。有趣的是，Hedgehog信号也在从纤维化到癌症的一系列成人疾病中进行了研究，最终在最近批准Hedgehog抑制剂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间室增殖和分化的作用以及这可能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中一种新的多能心肺前体细胞(CPP)。这些CPP克隆地产生肺血管系统和心脏的多个隔室。CPP中Hedgehog信号的缺失会导致肺血管发育不良，导致血管平滑肌细胞(VSMC)分化丧失。我还表明，Hedgehog信号继续激活成年肺血管中的外膜前体细胞，这些细胞能够在PAH动物模型中增殖和分化为VSMCs。这些结果表明，CPP和外膜细胞分别是正常发育和异常血管重塑中的VSMC前体，两者都由Hedgehog信号激活。因此，我推测Shh通过促进VSMC前体细胞的增殖和分化，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。我将通过检测VSMC前体细胞中Hedgehog缺失在胚胎肺血管发育和PAH动物模型中的作用来解决这一假设。这一提议产生的机械性理解可能为以Hedgehog通路为靶向治疗PAH患者提供强有力的理由。此外，成功完成这项提议将为我提供关键的培训，使我成为一名肺血管生物学和疾病的独立研究员。