Mechanisms linking insulin resistance to brain structure, pathology, and function

胰岛素抵抗与大脑结构、病理和功能的联系机制

• 批准号: 9084655
• 负责人: REXFORD S. AHIMA
• 金额: $ 63.85万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084655
• 关键词: 5' -AMP-activated protein kinase; Address; Adipocytes; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Autopsy; Brain; Brain Diseases; Brain Pathology; Cerebral Infarction; Cerebrovascular Disorders; Cessation of life; Clinical; Clinical Data; Cognition; Cognitive; Communities; Complex; Data; Dendritic Spines; Disease; Functional disorder; Future; Goals; Health; Hippocampus (Brain); Hormones; Human; Impaired cognition; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; JAK2 gene; Knowledge; Lead; Leptin; Life Style; Link; Measures; Mediator of activation protein; Metabolic; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathologic; Pathology; Pathway interactions; Persons; Phosphorylation; Presynaptic Terminals; Public Health; Publishing; Receptor Activation; Religion and Spirituality; Research; Research Priority; STAT3 gene; Scientist; Signal Pathway; Signal Transduction; Specimen; Structure; Synapses; System; Testing; Tissues; Variant; Vertebral column; Vesicle; Woman; Work; adipokines; adiponectin; amyloid pathology; base; brain tissue; clinical Diagnosis; cognitive function; density; improved; insulin sensitivity; insulin signaling; interest; leptin receptor; men; mild cognitive impairment; neuropathology; novel; novel therapeutics; postsynaptic; presynaptic; prevent; protein expression; receptor; receptor expression; response; tau Proteins; tau aggregation; tau function

DESCRIPTION (provided by applicant): Metabolic disturbances in particular type 2 diabetes mellitus (T2D), are common and increasing in incidence with contemporary lifestyles. T2D is associated with adverse health consequences, including impaired brain Yet, the causes and effects of insulin resistance in the brain are complex, as there are reciprocal interactions with other hormone signaling systems, in particular the adipokines (e.g., adiponectin and leptin) which strongly affect insulin sensitivity. Characterizing the molecular mechanisms that increase risk of AD for persons with insulin resistance is now of great scientific interest (PAS-11-029) and their elucidation may lead to novel therapeutic strategies. Insulin resistance, a core feature of T2D, may lead to increased brain pathology. T2D is modestly associated with cerebrovascular disease, but perhaps of even greater interest, recent data show brain insulin signaling abnormalities associated with AD pathology, specifically amyloid-ß and tau-related pathology as well. Furthermore, adipokine receptor expression abnormalities have also been found in AD. The overall goal of the proposed interdisciplinary collaborative project is to establish molecular mechanisms linking insulin, adopinectin, and leptin signaling in human brain, and determine how dysregulation in this network is associated with brain structure, pathology, and function, including AD and cognitive impairment. The proposed study will quantify markers of insulin, adiponectin, and leptin signaling, neurons and synapses, and use existing pathologic and clinical data from 200 community-dwelling women and men, with and without T2D and across a spectrum of cognitive function, who were well-characterized clinically and died and came to autopsy as participants in the Religious Orders Study (P30AG010161; R01AG015819). First, we will describe expression levels of brain insulin, adiponectin, and leptin pathway components in subjects with and without T2D (Aim 1). Then, using a novel ex-vivo stimulation paradigm in human postmortem tissue, we will experimentally test the stimulated responses and interactions of insulin and adipokine signaling in brain tissue (Aim 2). Finally, in the clinicopathologic translational component of the study, we will test the relations of insulin, adiponectin, and lepti signaling to brain structure (synaptic markers), pathology (amyloid-ß and tau), and function (cognition). Because insulin resistance is a common condition for which therapies are available, this study will break new ground in research of insulin and adipokine mechanisms in human brain, and show insulin resistance and adipokine dysfunction are associated with changes in the human brain at multiple levels, thus providing important data with potential to improve public health.

描述（由适用提供）：特定2型糖尿病（T2D）的代谢灾害很常见，并且使用现代生活方式的发病率增加。 T2D与不良健康后果有关，包括大脑受损，胰岛素抵抗在大脑中的原因和影响很复杂，因为与其他骑马信号系统存在相互相互作用，尤其是脂肪因子（例如脂联素和瘦素），这会严重影响胰岛素敏感性。现在表征了增加胰岛素抵抗患者AD风险的分子机制，现在具有极大的科学意义（PAS-11-029），其阐明可能会导致新的治疗策略。胰岛素抵抗是T2D的核心特征，可能导致大脑病理增加。 T2D与脑血管疾病有适度的相关，但可能具有更大的兴趣，最近的数据表明，脑胰岛素信号传导异常与AD病理学相关，特别是淀粉样蛋白 - β和与TAU相关的病理学。此外，在AD中也发现了脂肪因子受体表达异常。拟议的跨学科协作项目的总体目标是建立与人脑中胰岛素，采用蛋白和瘦素信号联系联系起来的分子机制，并确定该网络中的失调与大脑结构，病理学和功能（包括AD和认知障碍）如何相关。 The proposed study will quantify markers of insulin, adiponectin, and leptin signaling, neurons and synapses, and use existing pathological and clinical data from 200 community-dwelling women and men, with and without T2D and across a spectrum of cognitive function, who were well-characterized clinically and died and came to autopsy as participants in the Religious Orders Study (P30AG010161; R01AG015819）。首先，我们将描述有或没有T2D的受试者中脑胰岛素，脂联素和瘦素途径成分的表达水平（AIM 1）。然后，使用人类后组织中的新型外病毒刺激范式，我们将通过实验测试胰岛素和脑组织中胰岛素和脂肪因子信号传导的刺激反应和相互作用（AIM 2）。最后，在研究的临床病理转化成分中，我们将测试胰岛素，脂联素和LEPTI信号与大脑结构（突触标记），病理学（淀粉样蛋白 - tau）和功能（认知）的关系。由于胰岛素抵抗是可用疗法的常见病情，因此这项研究将在人脑中的胰岛素和脂肪因子机制研究中打破新的基础，并显示胰岛素抵抗和脂肪因子功能障碍与人脑在多个水平上的变化有关，从而提供具有潜力提高公共健康的重要数据。