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Effect of Insulin on Neuroplasticity and Cognitive Rehabilitation

胰岛素对神经可塑性和认知康复的影响

基本信息

批准号：
10232067
负责人：
Catrina Sims Robinson
金额：
$ 19.9万
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：
2014
资助国家：
美国
起止时间：
2014-06-02 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10232067
关键词：
Address Affect Animal Model Animals Anti-Inflammatory Agents Apoptotic Basic Science Brain Brain Injuries Brain region Centers of Research Excellence Cerebrospinal Fluid Clinic Clinical Investigator Cognition Cognitive Cognitive aging Data Dendritic Spines Diabetes Mellitus Diagnosis Diet Effectiveness Goals High Fat Diet Hippocampus (Brain)Hour Human Hyperinsulinism Insulin Insulin Resistance Insulin deficiency Ischemic Stroke Laboratories Lead Lesion Magnetic Resonance Imaging Memory Middle Cerebral Artery Occlusion Modeling Motor Mus Nervous System Physiology Neurologic Neuronal Plasticity Outcome Pathway interactions Peripheral Phenotype Play Property Proteins Recovery Recovery of Function Rehabilitation therapy Reporting Research Research Personnel Role Severities Stroke Structure Synapses Testing Therapeutic Time Tissues Translating Traumatic Brain Injury Work base behavior test brain health cognitive function cognitive rehabilitation comorbidity disability environmental enrichment for laboratory animals impaired glucose tolerance improved innovation motor recovery mouse model novel therapeutic intervention novel therapeutics post stroke programs stroke patient stroke recovery stroke rehabilitation stroke survivor synaptogenesis

项目摘要

There is a fundamental gap in understanding the importance of brain insulin levels in stroke recovery. This gap is important because of the significance of brain insulin with regard to neuroplasticity and the anti-inflammatory, anti-thrombotic, vasodilatory and anti-apoptotic properties of insulin, which play a vital role in recovery from brain injury. The long-term goal is to understand the role of comorbidities on brain health, specifically cognitive aging. The objective of this application is to investigate the role of reduced brain insulin and the therapeutic potential of intranasal insulin on long-term stroke recovery (4 months post-stroke). Insulin resistance, which is a common comorbidity among stroke survivors, leads to a deficiency of insulin in the brain. The central hypothesis is that increasing brain insulin levels will improve stroke recovery. This hypothesis is based on preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that brain insulin levels affect neuroplasticity, and intranasal insulin may offer a new therapeutic approach to improve recovery from stroke. This hypothesis will be tested by pursuing two specific aims: 1) Determine the impact of insulin deficiency in the brain on stroke recovery, and 2) Ascertain the therapeutic potential of intranasal insulin therapy on stroke recovery. Under Aim 1, stroke recovery (cognitive, sensorimotor and motor function) is assessed in a comorbid mouse model (high-fat diet) with brain insulin deficiency, and in a non-comorbid mouse model (standard diet) treated with intranasal insulin affibody molecules, which reduce brain insulin levels, following an ischemic stroke. Under the second aim, intranasal insulin therapy is implemented post-stroke to enhance rehabilitation-induced neuroplasticity and improve stroke recovery. The approach is innovative, because it utilizes a comorbid animal model of ischemic stroke, assesses long-term stroke recovery up to 4 months post-stroke, and uses intranasal insulin as a therapy to enhance neuroplasticity and improve stroke recovery. The proposed research is significant because it is expected to lead to the establishment of intranasal insulin as a potential therapy to enhance stroke recovery. Ultimately, the COBRE also will provide the unique opportunity to work with clinical investigators to translate this basic science research into the clinic.

对于脑胰岛素水平在中风恢复中的重要性的理解存在根本性的差距。这个差距很重要，因为脑胰岛素在神经可塑性和抗炎方面具有重要意义，胰岛素的抗血栓、血管舒张和抗细胞凋亡特性，在大脑恢复中发挥着至关重要的作用受伤。长期目标是了解合并症对大脑健康，特别是认知衰老的作用。该应用的目的是研究减少脑胰岛素的作用以及治疗潜力鼻内胰岛素对长期中风恢复（中风后 4 个月）的影响。胰岛素抵抗是一种常见的疾病中风幸存者的合并症导致大脑中胰岛素缺乏。中心假设是增加脑胰岛素水平将改善中风康复。这个假设是基于初步数据在申请人的实验室生产。拟议研究的基本原理是大脑胰岛素水平影响神经可塑性和鼻内胰岛素可能提供一种新的治疗方法来改善中风的恢复。该假设将通过追求两个具体目标来检验：1）确定胰岛素缺乏对机体的影响。大脑对中风恢复的影响，以及 2) 确定鼻内胰岛素治疗中风的治疗潜力恢复。在目标 1 下，以合并症评估中风恢复（认知、感觉运动和运动功能）脑胰岛素缺乏的小鼠模型（高脂肪饮食）和非共病小鼠模型（标准饮食）缺血性中风后，用鼻内胰岛素亲和体分子治疗，可降低脑胰岛素水平。第二个目标是在中风后实施鼻内胰岛素治疗，以增强康复诱导的效果。神经可塑性并改善中风恢复。该方法是创新的，因为它利用了共病动物缺血性中风模型，评估中风后长达 4 个月的长期中风恢复情况，并使用鼻内注射胰岛素作为增强神经可塑性和改善中风恢复的疗法。拟议的研究意义重大因为预计将导致鼻内胰岛素成为增强中风的潜在疗法恢复。最终，COBRE 还将提供与临床研究人员合作的独特机会将这项基础科学研究转化为临床。