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

基本信息

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
项目类别：
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

项目摘要

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.

目前针对由血管疾病引起的一系列认知障碍的治疗方案，称为血管对认知障碍和痴呆（VCID）的贡献有限，因为在我们的长期目标是阐明 VCID 的关键机制驱动因素。确定潜在的治疗靶点该应用的目的是探索潜在的机制。脑胰岛素在胰岛素抵抗和 VCID 模型中血管功能中的作用中心假设是。内皮蛋白酪氨酸磷酸酶 1B (PTP1B) 胰岛素转运水平升高导致脑血管功能障碍和 VCID 的信号传导该假设基于初步数据。拟议研究的基本原理是了解申请人的实验室。大脑胰岛素水平和信号传导降低的机制及其对血管功能的影响可能导致改善 VCID 的创新方法将通过追求两个具体目标来检验：1) 检验内皮细胞中 PTP1B 水平升高会降低脑胰岛素水平和信号传导的假设，降低血管功能，2) 检验增加大脑胰岛素水平从而恢复的假设目标 1 下，使用分子技术逆转 VCID 的脑血管功能和信号。将使用多光子成像在年轻人和中年人中评估毛细血管的结构/功能变化采用标准饮食或高脂饮食（胰岛素模型）的内皮细胞中缺乏 PTP1B 的转基因小鼠目标 2 下，通过测量脑血流量、神经元评估脑血管功能。通过评估生存、神经和感觉运动来评估活动、认知和功能恢复功能，将在青年和中年胰岛素抵抗小鼠 VCID（中脑中风的动脉闭塞模型）由于研究设计和组合而具有创新性。方法、鼻内胰岛素的使用，并关注 PTP1B 作为脑胰岛素减少的机制与 VCID 相关的水平/信号传导和血管功能障碍这项研究意义重大，因为它。预计将导致针对脑血管关键机制的治疗方法的开发功能障碍和 VCID。