Determinants of Aorta Heterogeneity

摘要 主动脉病变，包括动脉瘤、夹层和破裂，是HLBS的关键挑战 research.在过去的二十年里，我们不断资助对脊椎病的研究， 为脊椎病研究提供了许多机制性见解，包括一个新的 概念：主动脉在不同的胚胎起源中具有区域性特征 和细胞的功能。这个R35项目的总体假设是， 细胞起源赋予主动脉沿着长度的功能变化，包括 细胞外基质的稳定性，这反过来又有助于局部特异性病变。 在我们已经验证的许多小鼠模型中， 和表征了我们最初的单细胞转录组学和蛋白质组学数据也表明， 正常主动脉生物学和动脉病变异质性的新的潜在贡献者。三 本计划提出的主要主题是：（1）什么是结构和分子 导致沿着长度的生物学和病理生理学异质性的机制 大动脉的(2)细胞和细胞外异质性是否是区域特异性的基础？ 脊椎病？(3)信号通路、细胞外基质和细胞外基质之间的串扰 常驻主动脉细胞协调促进动脉病变的异质性？我们拥有强大 工具包括一系列试剂，多种经典和新的小鼠模型， 超声、MRI、活体显微镜、蛋白质组学和单细胞RNA测序 技术.除了脊椎病的研究，PI在这方面拥有超过30年的专业知识， 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，而是与广泛的疾病或综合征相关， 可能影响皮肤、肺、肾、脑、骨和其他器官。拟议的研究计划 将受益于寻求其他组织和器官的潜在贡献的灵活性， 病变，反之亦然，病变对其他组织和器官的影响。这 R35机制也将有利于PI在基础研究方面的实力，增强他与 临床竞技场的转化研究，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.