Targeting vascular pathology to treat age-related cognitive decline

针对血管病理学治疗与年龄相关的认知能力下降

• 批准号: 9192441
• 负责人: Aaron Friedman
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192441
• 关键词: Age Factors; Age-associated memory impairment; Aging; Albumins; Appearance; Behavior; Behavioral; Biological; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Clinic; Clinical; Dementia; Disease; Disease Progression; Early Intervention; Electrophysiology (science); Functional disorder; Future; Genetic; Histology; Human; Impaired cognition; Inflammatory; Lead; Learning; Memory; Memory impairment; Mentors; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurophysiology - biologic function; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plant Roots; Preventive treatment; Research; Research Training; Risk; Rodent; Signal Transduction; Staging; Structure; Symptoms; TGFB1 gene; Techniques; Testing; Therapeutic; Training; Transforming Growth Factor beta; Translating; Translational Research; age related; age related neurodegeneration; aged; career; clinically relevant; effective therapy; fundamental research; industry partner; inflammatory marker; innovation; new technology; novel; prevent; receptor; relating to nervous system; research study; response to injury; skills; small molecular inhibitor; small molecule; small molecule inhibitor; symptom management

PROJECT SUMMARY/ABSTRACT There are no effective treatments for age-related dementia. Many clinical approaches investigate the late-stage symptoms, after progression of severe neurodegeneration and appearance of memory dysfunction, and seek to manage these symptoms with drugs that boost neural function. The problem with this approach is that it only begins to treat patients after severe symptoms develop (after it is too late), and it is ineffective because it does not halt the underlying progression of disease. This proposal focuses on the earliest stages of pathology that lead to later neurodegeneration. We show that aging involves decline and breakdown of the vascular blood- brain barrier, which allows blood components to begin leaking into the brain. This causes an inflammatory injury response leading to neurodegeneration and aberrant neural function. I seek to target this early mechanism, to determine if blocking this inflammatory pathway can halt or reverse cognitive decline in aging. Using aged mice and a clinically relevant small molecule drug, I treat the target pathway and assess outcomes at the level of brain structure (decrease in inflammatory signaling and neurodegeneration), brain function (electrophysiological recording to detect aberrant brain activity), and behavior (improvements in a suite of memory tasks). By focusing on the root causes of disease, these experiments seek to show the potential of a new, preventative treatment aimed at the early stages of cognitive decline in aging. The training plan includes unique approaches to prepare me for independent research, including training in translational research (bringing fundamental research innovations from the lab to clinical and industrial applications).

项目概要/摘要 与年龄相关的痴呆症没有有效的治疗方法。许多临床方法研究晚期 出现严重神经退行性变和出现记忆功能障碍后的症状，并寻求 用增强神经功能的药物来控制这些症状。这种方法的问题在于它只能 在严重症状出现后（为时已晚）才开始治疗患者，并且它是无效的，因为它确实 不能阻止疾病的潜在进展。该提案侧重于病理学的最早阶段 导致后来的神经退行性变。我们发现衰老涉及血管血液的衰退和崩溃—— 脑屏障，允许血液成分开始渗漏到大脑中。这会导致炎症 损伤反应导致神经变性和神经功能异常。我力求尽早确定目标 机制，以确定阻断这种炎症途径是否可以阻止或逆转衰老过程中认知能力的下降。 使用老年小鼠和临床相关的小分子药物，我治疗目标途径并评估结果 在大脑结构水平（减少炎症信号和神经退行性变）、大脑功能 （电生理记录以检测异常的大脑活动）和行为（一系列的改进） 记忆任务）。通过关注疾病的根本原因，这些实验试图展示一种方法的潜力 针对衰老过程中认知能力下降的早期阶段的新的预防性治疗。培训计划包括 让我为独立研究做好准备的独特方法，包括转化研究培训 （将基础研究创新从实验室带到临床和工业应用）。