Atherogenic Induction of Neuroinflammation

神经炎症的动脉粥样硬化诱导

基本信息

批准号：
7844871
负责人：
NARAYAN R BHAT
金额：
$ 18.44万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844871
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animals Atherosclerosis Behavior Behavioral Biochemical Blood Vessels Brain C57BL/6 Mouse Cardiovascular Diseases Cells Cholesterol Cholesterol Homeostasis Cognitive Dementia Deposition Development Diabetes Mellitus Diet Dietary Cholesterol Disease Epidemiology Experimental Genetics Fatty acid glycerol esters Genetic Human Hypertension Immune Immune response Impaired cognition Inflammation Inflammatory Injury Intervention Knock-out Link Low Density Lipoprotein Receptor MAP Kinase Modules MAP2K3 gene MAPK14 gene Mediating Mediator of activation protein Memory Memory impairment Microglia Mitogen-Activated Protein Kinase Inhibitor Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathway interactions Performance Phosphotransferases Play Process Production Protein Kinase Risk Factors Role SB 203580 Short-Term Memory Signal Pathway Signal Transduction Testing Therapeutic Transgenic Mice Work amyloid precursor protein processing behavior test chemokine cytokine design experience feeding hypercholesterolemia improved in vivo kinase inhibitor member mitogen-activated protein kinase p38 mouse model mutant neuroinflammation neurotoxic public health relevance research study response upstream kinase vascular inflammation young adult

项目摘要

DESCRIPTION (provided by applicant): Inflammation is a common feature of a number of neurodegenerative diseases including Alzheimer's disease (AD) wherein inflammatory processes with significant contribution by vascular changes play a role in disease pathogenesis. Recent genetic, experimental and epidemiological findings further suggest a link between vascular risk factors including hypertension, diabetes, atherosclerosis and hypercholesterolemia and the development of AD. We propose that atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature, leading to AD-associated cognitive impairment. The proposed studies will examine if targeted disruption of a signaling pathway i.e., p38 MAP kinase, that is critically involved in inflammatory cascades would ameliorate hypercholesterolemia-induced neurovascular inflammation and cognitive impairment in a mouse model of AD. The experiments will use transgenic mice expressing mutant human amyloid precursor protein (APPTg) made deficient in a key member of the p38 MAP kinase cascade i.e., MAPK-activated protein kinase 2 (i.e., MAPKAP K2 or MK2) to test the hypothesis that this pathway signals atherogenic induction of neurovascular and inflammatory changes leading to AD-like dementia. The specific objectives are to determine if the kinase depletion and pharmacological intervention reduce dietary cholesterol-induced neuroinflammation and increased amyloid deposition in the APPTg mice with the outcome of an improved cognitive performance. The findings will have implications for designing therapeutic strategies targeted towards neurovascular inflammatory processes in AD. PUBLIC HEALTH RELEVANCE: Atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature leading to Alzheimer's disease (AD)-associated cognitive impairment. The proposed studies explore the idea that targeted disruption (genetic or pharmacological) of a key proinflammatory signaling pathway i.e., p38 MAP kinase, would ameliorate AD-like brain changes in a mouse model of AD with hypercholesterolemia. The findings would define a functional link between hypercholesterolemia-induced systemic immune response, brain function and behavior.

描述（由申请人提供）：炎症是许多神经退行性疾病（包括阿尔茨海默氏病（AD））的常见特征，其中炎症过程对血管变化的显着贡献在疾病发病机理中起作用。最近的遗传，实验和流行病学发现进一步表明，包括高血压，糖尿病，动脉粥样硬化和高胆固醇血症在内的血管危险因素之间存在联系，以及AD的发展。我们建议，由于饮食和/或遗传原因导致胆固醇稳态失调引起的动脉粥样硬化炎症可能会对脑血管系统产生不利影响，从而导致与AD相关的认知障碍。拟议的研究将检查是否有针对性的信号传导途径，即p38 MAP激酶（与炎症性级联反应非常重要的p38 MAP激酶，都会改善高胆固醇血症诱导的神经血管炎症和AD小鼠模型中的认知障碍。 The experiments will use transgenic mice expressing mutant human amyloid precursor protein (APPTg) made deficient in a key member of the p38 MAP kinase cascade i.e., MAPK-activated protein kinase 2 (i.e., MAPKAP K2 or MK2) to test the hypothesis that this pathway signals atherogenic induction of neurovascular and inflammatory changes leading to AD-like dementia.具体目标是确定激酶消耗和药理学干预是否会减少饮食中胆固醇诱导的神经炎症，并增加APPTG小鼠中淀粉样蛋白的沉积，并取得改善的认知表现。这些发现将对设计针对AD神经血管炎症过程的治疗策略具有影响。公共卫生相关性：由于饮食和/或遗传原因引起的胆固醇稳态失调引起的动脉炎可能会对脑血管产生不利影响，导致阿尔茨海默氏病（AD）相关的认知障碍。拟议的研究探讨了关键促炎信号传导途径的靶向破坏（遗传学或药理）的想法，即p38 MAP激酶会在患有高胆固醇血症的AD小鼠模型中改善AD类脑的变化。这些发现将定义高胆固醇诱导的全身免疫反应，脑功能和行为之间的功能联系。