Endothelial-Interstitial Interactions in Aortic Valve Homeostasis and Disease

主动脉瓣稳态和疾病中的内皮-间质相互作用

• 批准号: 9978112
• 负责人: Jonathan Talbot Butcher
• 金额: $ 49.71万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978112
• 关键词: 3-Dimensional; Affect; American; Animal Genetics; Animal Model; Apoptosis; Behavior; Biological; Biological Process; Biology; Bioreactors; Cell Communication; Cells; Characteristics; Cholesterol Homeostasis; Chronic; Coculture Techniques; Complex; Conflict (Psychology); Crystallization; Data; Diagnosis; Diagnostic; Diet; Disease; Disease Progression; Endothelial Cells; Endothelium; Environment; Extracellular Matrix; Female; Functional disorder; Gender; Generations; Genes; Health; Homeostasis; Human; Hydroxyapatites; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Lesion; Libido; Ligands; Literature; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Nitric Oxide; Osteoblasts; Oxidative Stress; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Population; Prevention; Process; Production; Regulation; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Stress; Stress Tests; Surface; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tracer; Transactivation; Transducers; aortic valve; aortic valve disorder; calcification; cell type; endothelial dysfunction; exome sequencing; genome wide association study; hemodynamics; improved; in vivo; innovation; insight; interstitial; interstitial cell; male; mortality risk; mouse genetics; notch protein; novel; osteogenic; overexpression; postnatal; progenitor; programs; receptor; restoration; stressor; targeted agent; therapeutic target; transcriptome sequencing

Project Summary Nearly 4 million Americans over 65 are living with calcific aortic valve disease (CAVD). CAVD pathogenesis is an active biological process that is untreatable by cholesterol metabolism modifying agents. There are currently no successful biological targets or therapeutic agents that specifically target CAVD. Aortic valve cusp homeostasis and pathogenesis is regulated by complex and poorly understood interactions between resident surface valve endothelial cells (VEC) and underlying valve interstitial cell (VIC). While almost all research has focused on VIC, which cannot be isolated from VEC that surround them and faithfully reveal the biology of aortic valves and pathobiology of CAVD, this research project aims to unravel the roles of VIC, VEC and their interactions, at cell and molecule levels, for valve homeostasis and CAVD. Our preliminary data using new valve lineage specific genetic animal models show that activation of NFκB (a master gene mediating inflammation) in VEC and VIC, or inaction of Notch1 (a major regulator of cell fate and behavior) in VEC only results in CAVD in mice. Further, our innovative 3D in vitro culture of VEC identifies that NFκB activation in VEC promotes VEC undergo endothelial-to-mesenchymal transformation and generate a novel mesenchymal progenitor T-VIC that calcifies matrix. These exciting new results motivate the hypothesis that NFκB-Notch1 control valve homeostasis and CAVD pathogenesis via prevention or generation of these T-VIC. This proposal will be tested in three Specific Aims. First we will elucidate the role of Notch-NFkB in VEC homeostasis and CAVD related pathogenesis (Aim 1). Then we will elucidate how T-VIC affect VEC and/or VIC phenotypes in 3D co-culture in novel CAVD-related conditions (Aim 2). Aim 3 will evaluate the efficacy of NFκB-Notch1 signaling rebalancing on CAVD initiation and progression in vivo via reduction of T-VIC. The completion of this project will generate significant information regarding intercellular regulation of aortic valve homeostasis and the CAVD pathogenic process. By revealing the unique phenotypic signatures of participation VEC and VIC, our study will also identify and motivated new molecular candidates that specifically target the cell specific characteristics of the CAVD process for potential diagnostic and therapeutic benefit.

项目概要 近 400 万 65 岁以上的美国人患有钙化性主动脉瓣疾病 (CAVD)。 CAVD的发病机制是 胆固醇代谢调节剂无法治疗的一种活跃的生物过程。有 目前还没有成功的专门针对 CAVD 的生物靶点或治疗药物。主动脉瓣尖角 体内平衡和发病机制受到居民之间复杂且知之甚少的相互作用的调节 表面瓣膜内皮细胞（VEC）和底层瓣膜间质细胞（VIC）。虽然几乎所有的研究都 重点关注 VIC，它与周围的 VEC 密不可分，忠实地揭示了 VIC 的生物学特性 主动脉瓣和 CAVD 的病理生物学，该研究项目旨在阐明 VIC、VEC 及其作用 细胞和分子水平上的相互作用，用于瓣膜稳态和 CAVD。我们使用新的初步数据 瓣膜谱系特异性遗传动物模型表明，NFκB（介导的主基因）的激活 VEC 和 VIC 中的炎症），或仅 VEC 中 Notch1（细胞命运和行为的主要调节因子）不活动 结果导致小鼠 CAVD。此外，我们创新的 VEC 3D 体外培养确定了 NFκB 激活 VEC促进VEC发生内皮细胞向间质细胞转化并产生新型间充质细胞 钙化基质的祖细胞 T-VIC。这些令人兴奋的新结果激发了这样的假设：NFκB-Notch1 通过预防或产生这些 T-VIC 来控制瓣膜稳态和 CAVD 发病机制。这个提议 将在三个具体目标中进行测试。首先，我们将阐明 Notch-NFkB 在 VEC 稳态中的作用以及 CAVD 相关发病机制（目标 1）。然后我们将阐明 T-VIC 如何影响 VEC 和/或 VIC 表型 在新的 CAVD 相关条件下进行 3D 共培养（目标 2）。目标 3 将评估 NFκB-Notch1 的功效 通过减少 T-VIC 在体内 CAVD 启动和进展的信号重新平衡。本次的完成 项目将产生有关主动脉瓣稳态的细胞间调节的重要信息 CAVD 致病过程。通过揭示参与 VEC 和 VIC 的独特表型特征， 我们的研究还将确定并激发专门针对细胞特异性的新分子候选物 CAVD 过程的特征，具有潜在的诊断和治疗益处。