Vascular Disease and Inflammation in Mice

小鼠的血管疾病和炎症

基本信息

批准号：
7633194
负责人：
RENEE C LEBOEUF
金额：
$ 40.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633194
关键词：
Address Affect Alzheimer&apos s Disease Animals Antiatherogenic Antibodies Apolipoprotein E Arteries Atherosclerosis Biology Cell Adhesion Molecules Cell Culture System Cellular biology Cholesterol Cholesterol Homeostasis Chronic Complex Crohn&apos s disease Cultured Cells Data Development Disease Enhancing Lesion Equilibrium Exposure to Family Family member Future Gene Expression Genes Goals Growth Factor Hematopoietic Individual Infectious Agent Inflammation Inflammatory Inflammatory Response Intervention Studies Knowledge Lesion Ligands Lymphocyte Measures Modeling Mus Pathway interactions Peptide Hydrolases Peritoneal Pharmacologic Substance Phenotype Play Principal Investigator Process Proteins Pulmonary Fibrosis Relative (related person)Rheumatoid Arthritis Role Severities Smooth Muscle Myocytes Staging TNF gene Testing Tissues Transgenic Mice Transgenic Organisms Transplantation Tumor Necrosis Factor-Beta Tumor Necrosis Factor-alpha Vascular Diseases Work Wound Healing atherogenesis bone cell type cytokine design human MPP1 protein human TNFRSF1A protein in vivo macrophage member mouse model pathogen prevent programs receptor response scavenger receptor selective expression therapy development tissue fixing tissue trauma transcriptional coactivator p75 tumor necrosis factor alpha receptor

项目摘要

DESCRIPTION (provided by applicant): Inflammatory processes are characterized by tissue- targeted accumulations of lymphocytes and the local elaboration of adhesion molecules, growth factors, proteases and cytokines. These processes originate in response to infectious agents and tissue trauma. Diseases such as rheumatoid arthritis, atherosclerosis, pulmonary fibrosis and Crohn's disease are examples of deleterious inflammation. Understanding the pivotal relationships in cell biology which control protection versus chronic damage is critical for preventing disease and treating millions of individuals with such diseases. Here, we study atherosclerosis as a model for inflammation. The long range goal is to understand how tumor necrosis factor alpha (TNF) receptors and ligands, TNF and lymphotoxin (LTa) contribute to atherosclerosis. Although studies implicate TNF as playing a deleterious role in atherosclerosis, our data suggests that its contribution is more complicated and dependent upon stage of atherosclerosis and cell types involved. In addition, we are the first group to show that LTa is present at the artery wall and loss of LTa also influences the progression of atherosclerosis. We are using mice deficient and transgenic in TNF ligands or receptors to demonstrate how these molecules contribute to atherogenesis and atheroprogression in three specific aims: (1) determine the role of TNF in cholesterol homeostasis in macrophages, (2) determine whether pharmaceutical inhibition or induced gene expression of TNF or LTa results in improvement in atherosclerosis severity, (3) determine the relative contribution of TNF family members derived from the hematopoietic compartment versus the fixed tissue compartment in atherosclerosis. Overall, this work will provide new and detailed information about the relative contributions of TNF molecules to atherosclerosis. We believe that detailed knowledge is still needed in the TNF field to realize the important goal of developing therapies which harness anti-atherogenic functions of TNF.

描述（由申请人提供）：炎症过程的特征是淋巴细胞的组织积累以及粘附分子的局部阐述，生长因子，蛋白酶和细胞因子。这些过程源于感染因子和组织创伤。类风湿关节炎，动脉粥样硬化，肺纤维化和克罗恩病等疾病是有害炎症的例子。了解控制保护与慢性损害的细胞生物学中的关键关系对于预防疾病和治疗数百万此类疾病的人至关重要。在这里，我们将动脉粥样硬化作为炎症模型。远距离目标是了解肿瘤坏死因子α（TNF）受体和配体，TNF和淋巴毒素（LTA）如何促进动脉粥样硬化。尽管研究暗示TNF在动脉粥样硬化中起着有害作用，但我们的数据表明，其贡献更为复杂，并且取决于动脉粥样硬化的阶段和所涉及的细胞类型。此外，我们是第一个表明LTA存在于动脉壁上的组，而LTA的损失也会影响动脉粥样硬化的进展。我们正在使用TNF配体或受体中缺乏和转基因的小鼠来证明这些分子在三个具体目标中如何有助于动脉粥样硬化和动脉粥样硬化：（1）确定TNF在巨噬细胞中胆固醇稳态中的作用TNF家族成员的相对贡献是源自造血室与动脉粥样硬化中固定组织室的相对贡献。总体而言，这项工作将提供有关TNF分子对动脉粥样硬化的相对贡献的新的详细信息。我们认为，在TNF领域仍然需要详细的知识来实现开发疗法的重要目标，这些疗法利用了TNF的抗动脉粥样硬化功能。