Determinants of Aorta Heterogeneity

摘要 动脉病变，包括动脉瘤、夹层和破裂，是HLBS的一个关键挑战。 研究。在过去的二十年里，我们不断地资助关于大动脉疾病的研究，我们 为大动脉病变的研究提供了许多机械论的见解，包括一项新的 概念：不同胚胎起源的大动脉具有区域性特征。 和细胞的功能。该R35计划的总体假设是 细胞起源赋予了沿主动脉长度的功能差异，包括 细胞外基质的稳定性，这反过来又有助于动脉病变的区域特异性。 在我们已经证实的许多小鼠模型中存在动脉病变的区域特异性 并以此为特征。我们最初的单细胞转录组和蛋白质组学数据也表明 导致正常主动脉生物学和主动脉病变异质性的新的潜在因素。三 本计划提出的主要主题是：(1)什么是结构和分子 导致生物和病理生理沿长度方向异质性的机制 (2)细胞和细胞外的异质性是动脉局部特异性的基础吗？ 主动脉病变？(3)信号通路、细胞外基质和相互间的串扰是如何 驻留的主动脉细胞协调以促进主动脉病变的异质性？我们有健壮的 工具包括一系列试剂，多种经典和新的鼠标模型， 超声、核磁共振、活体显微镜、蛋白质组学和单细胞RNA测序 技巧。除了大动脉疾病的研究外，PI还拥有30多年的 脂蛋白代谢、炎症和动脉粥样硬化研究领域。主动脉病变是 不是唯一的主动脉疾病，但与一系列疾病或综合征有关， 可影响皮肤、肺、肾、脑、骨等器官。建议的研究计划 将受益于寻求其他组织和器官的潜在贡献的灵活性 主动脉病变对其他组织和器官的影响，反之亦然。这 R35机制也将有利于PI在基础研究方面的实力，加强他与 在临床领域进行转化性研究，培养下一代科学家。

Abstract Aortopathies, including aneurysms, dissection, and rupture, represent a key challenge in HLBS research. In the past twenty years of our continuously funded research on aortopathies, we have contributed to many mechanistic insights into the aortopathy research including a new concept: There are regional characteristics of the aorta in regard to diverse embryonic origins and functions of cells. The overall hypothesis of this R35 program is that heterogeneity of cellular origins imparts functional variances along the length of the aorta, including diversity of extracellular matrix stability, which in turn contributes to regional specificity of aortopathies. Regional specificity of aortopathies is present in many mouse models that we have validated and characterized. Our initial single cell transcriptomic and proteomic data have also implicated new potential contributors to heterogeneity of the normal aortic biology and aortopathies. Three major themes are proposed in this program: (1) What are the structural and molecular mechanisms that contribute to biological and pathophysiological heterogeneity along the length of the aorta? (2) Are cellular and extracellular heterogeneity a basis for regional specificity of aortopathies? (3) How do signaling pathways, extracellular matrix, and crosstalk between resident aortic cells coordinate to promote the heterogeneity of aortopathies? We have robust tools including a spectrum of reagents, multiple classic and new mouse models, ultrasonography, MRI, intravital microscopy, proteomics, and single cell RNA sequencing techniques. In addition to aortopathy research, the PI has more than 30-year expertise in the fields of lipoprotein metabolism, inflammation, and atherosclerosis research. Aortopathies are not a sole aortic disease, but is associated with a wide range of diseases or syndromes that may affect skin, lung, kidney, brain, bone, and other organs. The proposed research program will benefit from the flexibility to pursue potential contributions of other tissues and organs to aortopathies, and vice versa the influences of aortopathies on other tissues and organs. This R35 mechanism will also benefit the PI’s strength in basic research, enhance his interaction with the translational research in the clinical arena, and train the next generation of scientists.