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Novel Inflammatory Pathway of Aged-Enhanced Atherosclerosis

老年性动脉粥样硬化的新炎症途径

基本信息

批准号：
9266471
负责人：
Daniel Robert Goldstein
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266471
关键词：
Adaptor Signaling Protein Adoptive Transfer Affect Age Aging Aorta Arterial Fatty Streak Atherosclerosis Autophagocytosis Autophagosome Biological Assay Biological Models CCL2 gene Cardiovascular Diseases Cell Aging Cell Culture Techniques Chemotactic Factors Chemotaxis Chronic Consequentialism DNA Development Disabled Persons Disease Exhibits Experimental Models Failure Healthcare Immune Impairment In Vitro Inflammation Inflammatory Inflammatory Response Link Mitochondria Modeling Molecular Monocytosis Mus Muscle Cells Older Population Oxygen Pathway interactions Peripheral Pharmacology Phenotype Play Production Reactive Oxygen Species Recruitment Activity Reporter Risk Risk Factors Role Testing Toll-like receptors Vascular Smooth Muscle Work aged atherogenesis clinical care cohort in vivo Model inflammatory milieu inhibitor/antagonist insight macrophage monocyte new therapeutic target novel novel therapeutics osteopontin public health relevance

项目摘要

DESCRIPTION (provided by applicant): Chronic low-level inflammation is a hallmark of aging. However, the mechanistic links between chronic inflammation and cardiovascular diseases are not fully understood. As aging is one of the strongest independent risk factors for atherosclerosis, understanding this link is of critical importance to the clinical care of our ever increasing population of older people. In an experimental model of atherosclerosis (i.e., LDLr -/- mice), we found that aging leads to larger atherosclerotic lesions; increased production of macrophage chemo-attractants, CCL2 and osteopontin; peripheral monocytosis; and an increase in macrophage recruitment into the aorta. Our prior work demonstrates that without atherosclerosis, aged vascular smooth muscle cells (VSMC) contribute to the aortic inflammatory milieu by producing increased CCL2 and osteopontin. Importantly, we showed that the production of these inflammatory molecules depends on MyD88, an innate immune adaptor protein downstream of the Toll like receptors. We also found that aging impairs autophagosome formation within VSMC and is accompanied by increased mitochondrial mass and reactive oxygen species. Taken together, these findings suggest that damaged mitochondria accumulate in aging VSMC due to reduced autophagy, leading in turn to a buildup of mitochondrial components that activate MyD88 to enhance atherosclerosis. To test this hypothesis, we will use a new model system in which MyD88 is selectively and inducibly deleted within VSMC of aging atherosclerotic prone mice to examine the extent by which MyD88 expression within VSMC controls age-enhanced macrophage recruitment into the aorta and atherosclerosis. We will also use mice in which autophagy is disabled within VSMC, to determine if autophagy in VSMC controls basal inflammation, monocyte recruitment into the aorta, and the development of atherosclerosis. Our proposal will yield critical insights into how aging impacts inflammatory responses in VSMC to enhance atherosclerosis. Our findings may contribute to the development of novel therapies for atherosclerosis in the older population.