Determinants of Aorta Heterogeneity

主动脉异质性的决定因素

基本信息

批准号：
10618144
负责人：
Alan Daugherty
金额：
$ 83.96万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618144
关键词：
Affect Aneurysm Aorta Aortic Diseases Atherosclerosis Basic Science Biological Biology Brain Cell physiology Cells Characteristics Clinical Data Disease Dissection Embryo Extracellular Matrix Funding Heterogeneity Inflammation Kidney Length Life Lipoproteins Lung Magnetic Resonance Imaging Medical Metabolism Molecular Operative Surgical Procedures Organ Pathogenesis Patient observation Pharmaceutical Preparations Proteomics Reagent Research Rupture Scientist Signal Pathway Skin Specificity Syndrome Techniques Therapeutic Tissues Training Translational Research Ultrasonography bone extracellular flexibility insight intravital microscopy mouse model next generation novel programs single-cell RNA sequencing tool transcriptomics

Affect Aneurysm Aorta Aortic Diseases Atherosclerosis Basic Science Biological Biology Brain Cell physiology Cells Characteristics Clinical Data Disease Dissection Embryo Extracellular Matrix Funding Heterogeneity Inflammation Kidney Length Life Lipoproteins Lung Magnetic Resonance Imaging Medical Metabolism Molecular Operative Surgical Procedures Organ Pathogenesis Patient observation Pharmaceutical Preparations Proteomics Reagent Research Rupture Scientist Signal Pathway Skin Specificity Syndrome Techniques Therapeutic Tissues Training Translational Research Ultrasonography bone extracellular flexibility insight intravital microscopy mouse model next generation novel programs single-cell RNA sequencing tool transcriptomics

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项目摘要

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.

抽象的主动脉疾病，包括动脉瘤，解剖和破裂，代表了HLBS的关键挑战研究。在过去的二十年中，我们对主动脉病变的研究持续研究，我们已经为主动脉粥样研究的研究做出了许多机械见解，包括新的概念：关于潜水胚胎的主动脉的区域特征和细胞的功能。该R35程序的总体假设是细胞起源沿主动脉长度不可能的功能差异，包括多样性细胞外基质稳定性，进而有助于主动脉疾病的区域特异性。在许多鼠标模型中都介绍了主动脉疾病的区域特异性，我们已经验证了并描述了。我们最初的单细胞转录组和蛋白质组学数据也已实现正常主动脉生物学和主动脉疾病的异质性的新潜在贡献者。三该程序提出了主要主题：（1）结构和分子是什么沿长度有助于生物学和病理生理异质性的机制主动脉？（2）是细胞和细胞外异质性的基础主动脉疾病？（3）如何信号通路，细胞外基质和串扰驻留主动脉细胞协调以促进主动脉疾病的异质性？我们有强大的包括一系列试剂，多个经典和新鼠标模型的工具，超声检查，MRI，插入显微镜，蛋白质组学和单细胞RNA测序技术。除了主动脉粥样硬化研究外，PI在30年以上的专业知识中脂蛋白代谢，感染和动脉粥样硬化研究领域。主动脉疾病是不是唯一的主动脉疾病，而是与多种疾病或综合症有关的可能会影响皮肤，肺，肾脏，脑，骨骼和其他器官。拟议的研究计划将从灵活性中受益于其他时间和器官的潜在贡献主动脉疾病，反之亦然，主动脉疾病对其他时间和器官的影响。这 R35机制还将受益于PI在基础研究中的优势，增强他与临床领域的转化研究，并培训下一代科学家。