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: 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
• 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

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.

摘要：胚胎程序的重述是多种表现为异常细胞增殖的疾病的特征。揭示胚胎血管发育的生物学复杂性有可能更好地理解成人血管疾病（如肺动脉高压（PAH））的发病机制。PAH患者的血管室表现出异常的增殖能力，导致肺血管的不适应重构和血管管腔的闭塞。在正常静止的组织室（如肺血管）中，异常增殖常常会重新激活胚胎程序，从而在正常发育过程中驱动增殖和分化。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控因子。有趣的是，从纤维化到癌症，刺猬信号也在广泛的成人疾病中得到了研究，最近终于批准了一种用于治疗基底细胞癌的刺猬抑制剂。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种新型多能心肺祖细胞（CPPs）。这些cps克隆地产生肺血管和心脏的多个腔室。CPPs中Hedgehog信号的缺失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，在PAH动物模型中，刺猬信号继续激活成人肺血管中的外体细胞，这些外体细胞能够增殖并分化为VSMCs。这些数据表明，CPPs和外体细胞分别是正常发育和异常血管重构中的VSMC祖细胞，它们都被Hedgehog信号激活。因此，我假设Shh通过促进VSMC祖细胞的增殖和分化，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。我将通过在胚胎肺血管发育和PAH动物模型中检测VSMC祖细胞中Hedgehog基因缺失的影响来解决这一假设。从这一建议中产生的机制理解可以为PAH患者的治疗靶向Hedgehog途径提供强有力的理论依据。此外，成功完成这项提案将为我提供成为肺血管生物学和疾病独立研究者的关键培训。