Pathophysiology of the Endothelium

内皮细胞的病理生理学

基本信息

批准号：
8300916
负责人：
FRANCIS W. LUSCINSKAS
金额：
$ 230.02万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300916
关键词：
1,2-diacylglycerol A kinase anchoring protein AKAP9 gene Actins Acute Address Adhesions Adhesives Affect Animal Model Animals Atherosclerosis Attention Autoimmunity Biochemical Biological Biological Assay Blood Vessels CD47 gene Calcium Cardiovascular Diseases Cell Adhesion Cell Culture Techniques Cell Line Cell membrane Cell-Cell Adhesion Cells Cellular biology Chronic Confocal Microscopy Cyclic AMP Cytoskeleton Data Defect Dermal Diabetes Mellitus Diglycerides Disease Employee Strikes Endothelial Cells Endothelium Endotoxins Experimental Autoimmune Encephalomyelitis Functional disorder Funding Goals Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Heart Hemostatic Agents Hemostatic function Histopathology Homeostasis Hormones Human Hybridomas IL17 gene ITGB2 gene Immune Immune System Diseases Immune response Immune system Immunohistochemistry Immunologics In Vitro Inflammation Inflammatory Inflammatory Response Integrin alpha4beta1 Integrins Intercellular adhesion molecule 1 Interferons Interleukin-17 Investigation Knockout Mice Laboratories Leukocytes Life Ligands Lymphocyte Lymphocyte Subset Mediating Mediator of activation protein Metabolic syndrome Modeling Molecular Molecular Genetics Mononuclear Leukocytes Morphology Mus Myocardial Infarction Organ Pathogenesis Pathway interactions Physiological Play Process Property Publications Reaction Recording of previous events Regulation Role SHPS-1 protein Signal Pathway Signal Transduction Signal Transduction Pathway Site Stroke T-Lymphocyte T-Lymphocyte Subsets Technology Thrombin Thrombosis Thrombospondin 1 Tissues Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities Work Wound Healing allograft rejection base cell motility cellular imaging chemokine cytokine in vitro Model in vivo insight intravital microscopy macromolecule migration molecular imaging mutant new therapeutic target programs receptor research study response scaffold thrombospondin 2

项目摘要

Inflammation is a key component of cardiovascular diseases and related pathophysiological processes, including atherosclerosis, autoimmunity, allograft rejection, the diabetes-metabolic syndrome, hemostasis and thrombosis, and wound healing. The vascular endothelium plays an active and vital role in regulating inflammatory responses and in maintaining homeostasis of the innate and adaptive immune systems. Two basic functions of the endothelium, particularly important in the context of inflammation, are the regulation of leukocyte recruitment and vascular permeability, both of which involve coordinated interactions of cell-cell adhesion/junctional molecules and the actin cytoskeleton. Dysregulation of these endothelial functions promotes inflammatory disease processes. Since its inception 30 years ago, this Program Project has combined cell and molecular biological, biochemical, morphological, molecular genetic, and experimental pathological approaches in in vitro cell culture and in vivo animal models to gain new insights into the active role of vascular endothelium in inflammation. In this amended renewal application, Project 1 will study the contribution of endothelial CD47 and its ligands Signal Regulatory Proteins and thrombospondin, as well as leukocyte CD47 dependent regulation of VLA-4 and LFA-1 integrin adhesion, in the recruitment of inflammatory mononuclear leukocytes into sites of chronic inflammation. Project 2 will examine the mechanisms by which endothelium selectively regulates recruitment of the IL17- and IFN-y producing subsets of T lymphocytes into tissues. Project 3 will determine how endothelial barrier function and leukocyte integrin-mediated adhesion may be selectively regulated by the subcellular compartmentalization of signaling by the intracellular mediator cAMP and its effectors molecules. In support of the scientific goals of these projects. Core A (Cell Biology) will provide well characterized vascular cell cultures (human, mouse, wildtype and mutant); monoclonal hybridoma cells and leukocyte cell lines; Core B (Morphology) will assist in immunohistochemistry and histopathology of mouse tissues; Core C (Physiological and Molecular Imaging) will support intravital and confocal microscopy studies as well as in vitro leukocyte-endothelial adhesion studies under defined flow conditions. Core D will provide administrative, secretarial and laboratory management support for the Program. The results of these proposed studies should yield valuable new insights into how vascular endothelial cells actively participate in the regulation of the inflammatory process, which is central to so many pathophysiological conditions that affect the heart and blood vessels (e.g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases.

炎症是心血管疾病和相关病理生理过程的关键组成部分，包括动脉粥样硬化、自身免疫、同种异体移植排斥、糖尿病代谢综合征、止血和血栓形成以及伤口愈合。血管内皮在调节炎症反应以及维持先天性和适应性免疫系统的稳态方面发挥着积极而重要的作用。内皮的两个基本功能，在炎症情况下特别重要，是白细胞募集和血管通透性的调节，这两者都涉及细胞-细胞粘附/连接分子和肌动蛋白细胞骨架的协调相互作用。这些内皮功能的失调会促进炎症性疾病的进程。自30年前启动以来，该项目在体外细胞培养和体内动物模型中结合了细胞和分子生物学、生化、形态学、分子遗传学和实验病理学方法，对血管内皮在血管生成中的积极作用有了新的认识。炎。在此修订的更新申请中，项目 1 将研究内皮 CD47 及其配体信号调节蛋白和血小板反应蛋白的贡献，以及 VLA-4 和 LFA-1 整合素粘附的白细胞 CD47 依赖性调节，在炎症单核白细胞募集到慢性炎症部位。项目 2 将研究内皮细胞选择性调节产生 IL17 和 IFN-γ 的 T 淋巴细胞亚群募集到组织中的机制。项目 3 将确定如何通过细胞内介质 cAMP 及其效应分子的信号传导亚细胞区划来选择性调节内皮屏障功能和白细胞整合素介导的粘附。支持这些项目的科学目标。核心A（细胞生物学）将提供特征明确的血管细胞培养物（人类、小鼠、野生型和突变型）；单克隆杂交瘤细胞和白细胞细胞系；核心B（形态学）将协助小鼠组织的免疫组织化学和组织病理学； Core C（生理和分子成像）将支持活体和共聚焦显微镜研究以及规定流动条件下的体外白细胞-内皮粘附研究。核心 D 将为该计划提供行政、秘书和实验室管理支持。这些拟议研究的结果应该对血管内皮细胞如何积极参与炎症过程的调节产生有价值的新见解，炎症过程对于影响心脏和血管的许多病理生理状况（例如心脏病发作和中风）至关重要。以及身体的其他器官和组织。这些机制见解可能有助于确定治疗多种炎症性疾病的新治疗靶点。