Targeting brain insulin to improve stroke-related vascular contributions to cognitive impairment and dementia

针对脑胰岛素改善中风相关血管对认知障碍和痴呆的影响

• 批准号: 10484278
• 负责人: Catrina Sims Robinson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10484278
• 关键词: Adherence; Animal Experimentation; Animal Model; Blood - brain barrier anatomy; Blood Cells; Blood Vessels; Blood capillaries; Blood flow; Brain; Bypass; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Core-Binding Factor; Data; Decision Making; Development; Diabetes Mellitus; Diet; Endocytosis; Endothelial Cells; Endothelium; Functional disorder; Goals; Guidelines; High Fat Diet; Hippocampus; Hyperinsulinism; Impaired cognition; Impairment; Industry; Insulin; Insulin Receptor; Insulin Resistance; Ischemia; Ischemic Stroke; Laboratories; Measures; Mediating; Memory; Methods; Middle Cerebral Artery Occlusion; Modeling; Molecular; Motor; Mus; Nervous System Physiology; Neurologic; Neuronal Plasticity; Neurons; Outcome; Patients; Process; Protein Dephosphorylation; Receptor Signaling; Recommendation; Recovery; Recovery of Function; Research; Research Design; Risk Factors; Role; Saline; Sensorimotor functions; Signal Transduction; Stroke; Structure; Survival Rate; Techniques; Testing; Thalamic structure; Therapeutic; Thinking; Transgenic Mice; Tyrosine; Tyrosine Phosphorylation; Vascular Diseases; Vascular Endothelial Cell; Vibrissae; blood-brain barrier function; brain cell; brain endothelial cell; cerebrovascular; cognitive function; combat; comorbidity; improved; innovation; insulin signaling; interest; middle age; mouse model; multiphoton imaging; new therapeutic target; post stroke; prevent; protein tyrosine phosphatase 1B; stroke model; stroke survivor; stroke therapy; targeted treatment; therapeutic target; therapy development; vascular cognitive impairment and dementia; vascular risk factor

Current treatment options for the spectrum of cognitive disorders brought about by vascular disease, termed vascular contributions to cognitive impairment and dementia (VCID), are limited due to a fundamental gap in understanding the underlying mechanisms. Our long-term goal is to elucidate key mechanistic drivers of VCID to identify potential therapeutic targets. The objective of this application is to explore the mechanisms underlying the role of brain insulin in vascular function in a model of insulin resistance and VCID. The central hypothesis is that elevated levels of endothelial protein tyrosine phosphatase 1B (PTP1B) reduces insulin transport and signaling contributing to cerebrovascular dysfunction and VCID. This hypothesis is based on preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that understanding the mechanisms underlying reduced brain insulin levels and signaling and its impact on vascular function may lead to innovative approaches to ameliorate VCID. This hypothesis will be tested by pursuing two specific aims: 1) test the hypothesis that elevated levels of PTP1B in endothelial cells reduces brain insulin levels and signaling, thereby reducing vascular function and 2) test the hypothesis that increasing brain insulin levels restores cerebrovascular function reversing VCID. Under Aim 1, insulin levels/signaling using molecular techniques and structural/functional changes using multiphoton imaging in capillaries will be assessed in young and middle-aged transgenic mice lacking PTP1B in endothelial cells on either a standard diet or high-fat diet (model of insulin resistance). Under Aim 2, cerebrovascular function, assessed via measuring cerebral blood flow, neuronal activity, and cognition, and functional recovery, assessed via evaluating survival, neurological, and sensorimotor function, will be examined in a young and middle-aged insulin resistant mouse model of VCID (middle cerebral artery occlusion model of stroke). The approach is innovative because of the study design, combination of methods, use of intranasal insulin, and focus on PTP1B as a mechanism underlying reduced brain insulin levels/signaling and vascular dysfunction associated with VCID. The proposed research is significant because it is expected to lead to the development of therapies targeted to key mechanisms underlying cerebrovascular dysfunction and VCID.

目前由血管疾病带来的认知障碍谱的治疗选择，称为 对认知障碍和痴呆（VCID）的血管贡献受到限制，这是由于基本差距 了解基本机制。我们的长期目标是阐明VCID的关键机械驱动器 确定潜在的治疗靶标。该应用的目的是探索基本机制 脑胰岛素在血管功能中的作用在胰岛素抵抗和VCID模型中的作用。中心假设是 升高的内皮蛋白酪氨酸磷酸酶1B（PTP1B）的水平降低了胰岛素的转运和 信号导致脑血管功能障碍和VCID。该假设基于初步数据 在申请人的实验室中生产。拟议研究的理由是了解 降低大脑胰岛素水平和信号传导及其对血管功能的影响的机制可能导致 为了改善VCID的创新方法。该假设将通过追求两个具体目标来检验：1） 检验以下假设：内皮细胞中PTP1B水平升高可降低脑胰岛素水平和信号传导， 从而降低血管功能并2）检验以下假设：增加脑胰岛素水平恢复 脑血管功能逆转VCID。在AIM 1下，使用分子技术的胰岛素水平/信号传导和 在毛细血管中使用多光子成像的结构/功能变化将在年轻和中年进行评估 在标准饮食或高脂饮食中，内皮细胞中缺乏PTP1B的转基因小鼠（胰岛素模型 反抗）。在AIM 2下，通过测量脑血流，神经元评估脑血管功能 通过评估生存，神经系统和感觉运动评估的活动，认知和功能恢复 功能，将在VCID的年轻和中年胰岛素耐药的小鼠模型中进行检查（中大脑 中风的动脉闭塞模型）。该方法是创新的，因为研究设计，结合 方法，鼻内胰岛素的使用以及专注于PTP1B作为降低脑胰岛素的机​​制 与VCID相关的水平/信号传导和血管功能障碍。拟议的研究很重要，因为它 预计将导致针对脑血管基础的关键机制的疗法的发展 功能障碍和VCID。