Brain protein alteration by vascular overexpressed miRNA (BravomiR)

血管过度表达 miRNA (BravomiR) 改变脑蛋白

基本信息

批准号：
10392051
负责人：
DEBOMOY K LAHIRI
金额：
$ 43.55万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2022-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392051
关键词：
Abeta synthesis Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease risk American Amyloid beta-Protein Animal Model Autopsy Biochemical Blood Vessels Brain Cell Culture Techniques Cells Chronic Disease Data Dementia Depressed mood Diabetes Mellitus Diagnosis Disease Disease Resistance Epidemiology Etiology Future Goals Human Hyperglycemia Inflammation Injections Insulin Resistance Knowledge Laboratories Literature Measurement Measures Messenger RNA Metabolic syndrome MicroRNAs Modeling Molecular Mus Neurofibrillary Tangles Neurons Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathology Pathway interactions Peripheral Physicians Play Prediabetes syndrome Proteins Reagent Regulation Regulatory Pathway Reporter Reporting Research Design Role Sample Size Sampling Scientist Senile Plaques Synapses Testing Time Transgenic Model Transgenic Organisms Translations Untranslated RNA Untranslated Regions Vascular Endothelial Cell Vascular Endothelium age related base comorbidity cost design diabetic disorder control experience experimental study expression cloning follow-up hyperphosphorylated tau induced pluripotent stem cell innovation insulin signaling metabolomics mild cognitive impairment mind control mouse model network dysfunction neuroblastoma cell neuroinflammation neuropathology neurovascular non-genetic novel overexpression quantum tau Proteins tau aggregation tau-1 therapeutic miRNA transgenic model of alzheimer disease translational impact

项目摘要

Significance: Alzheimer’s disease (AD) is the most common form of age-related dementia, affecting over 5.8 million Americans. Diabetes affects 34 million Americans (90-95% of which is type 2 diabetes, T2D), of which 1.5 million were newly diagnosed in the previous year. Most of these “new” cases were 45-64 years old, also important to pre-AD etiology. About 88 million have pre-diabetes. Since comorbidity is common in humans, an integrated study of AD and diabetes would have significant translational impact. Our goal to unveil specific shared AD/T2D regulatory pathways is significant to lay groundwork for “co-treatment” of comorbid conditions Rationale: Understanding co-regulation of the T2D-AD axis will be beneficial for two widespread interlinked chronic disorders. AD neuropathology primarily consists of neuritic plaques of amyloid-β (Aβ) peptide, neuro- fibrillary tangles of hyperphosphorylated tau (τ), neuroinflammation, and synaptic loss. Hyperglycemia increases Aβ production. Other pathways that operate “through” T2D and “into” AD include brain insulin resistance, and diabetes-triggered elevation of inflammation and oxidative stress, exacerbating Aβ and tau aggregation. Such shared dyshomeostasis suggests shared dysregulation. One such dysregulatory avenue would be microRNAs (miRNA), small non-coding RNAs that modulate translation of proteins from mRNA. Hypothesis: Two specific miRNA species that are dysregulated in T2D (miR146a, miR200b) are also dysregulated in AD, and significant AD-associated immediate and downstream effects accompany this co- dysregulation. Approach: Combining non-genetic T2D animal models, pertinent (human neuronal and human neurovascular) culture manipulation, and human AD samples (and control brains). Aim 1: Test the hypothesis that T2D disruption of CNS protein levels is rescued by vascular expression of miR200b/miR146a. We will test disruption of protein levels in mouse brains and rescue by miR146a and 200b. Aim 2: Test the hypothesis that selected miRNAs directly interact with 3’-UTRs of AD-associated mRNAs. We will characterize miR146a and 200b effects on AD-related proteins and show that activities of miR200b and 146a in mouse models have counterparts in human-origin cells when treated with human miR200b and/or 146a. Aim 3: Test the hypothesis that T2D and AD similarly disrupt selected miRNAs in human brains. We will determine the extent to which miR200b and -146 are perturbed in T2D, AD, and T2D+AD autopsy brain samples. Impact & Future Plan: We will discover and manipulate a network of shared miRNA dysregulation in all stages of T2D/AD, allow regulatory progression of early disease stages to be known in parallel. We will study neuro- pathology in miRNA overexpression/AD cross transgenic models and induced T2D in AD Tg models. We will design experiments to track shared biochemical progression of T2D and AD, as well as T2D that does not progress into AD. The overall impact is to develop intentional regulation of brain proteins alteration via vascular overexpressed miRNA through peripheral administration.

意义：阿尔茨海默病 (AD) 是最常见的与年龄相关的痴呆症，影响超过 5.8 岁糖尿病影响着 3400 万美国人（其中 90-95% 是 2 型糖尿病，T2D），其中去年新增确诊病例 150 万人，其中大多数年龄在 45-64 岁之间。大约 8800 万人患有糖尿病前期，因为合并症在人类中很常见。 AD 和糖尿病的综合研究将产生重大的转化影响，我们的目标是揭示具体的共同点。 AD/T2D 监管途径对于为共病“共同治疗”奠定基础具有重要意义理由：了解 T2D-AD 轴的共同调节将有利于两个广泛相互关联的疾病 AD 神经病理学主要由淀粉样蛋白 (Aβ) 肽、神经-斑块组成。过度磷酸化 tau (τ) 纤维缠结、神经炎症和高血糖增加。 “通过”T2D 并“进入”AD 的其他途径包括大脑胰岛素抵抗和糖尿病引发炎症和氧化应激升高，加剧 Aβ 和 tau 蛋白聚集。共同的体内平衡失调表明共同的失调途径之一就是 microRNA。 (miRNA)，调节 mRNA 蛋白质翻译的小非编码 RNA。假设：在 T2D 中失调的两种特定 miRNA（miR146a、miR200b）也与 AD 失调，以及与 AD 相关的显着的直接和下游效应伴随着这种共同作用方法：结合相关的非遗传性 T2D 动物模型（人类神经和人类）神经血管）培养操作和人类 AD 样本（和对照大脑）。目标 1：检验以下假设：T2D 中枢神经系统蛋白水平的破坏可通过血管表达来挽救我们将测试 miR200b/miR146a 对小鼠大脑中蛋白质水平的破坏以及 miR146a 和 200b 的拯救。目标 2：测试所选 miRNA 与 AD 相关 mRNA 的 3'-UTR 直接相互作用的假设。将表征 miR146a 和 200b 对 AD 相关蛋白的影响，并显示 miR200b 和 146a 的活性当用人 miR200b 和/或 146a 处理时，小鼠模型中的供体为人源细胞。目标 3：检验 T2D 和 AD 类似地破坏人脑中选定的 miRNA 的假设。确定 miR200b 和 -146 在 T2D、AD 和 T2D+AD 尸检脑样本中受到干扰的程度。影响和未来计划：我们将发现并操纵所有阶段共享 miRNA 失调的网络 T2D/AD 的研究，使我们能够同时了解早期疾病阶段的调节进展。 miRNA 过表达/AD 交叉转基因模型中的病理学以及 AD Tg 模型中诱导的 T2D。设计实验来追踪 T2D 和 AD 的共同生化进展，以及不存在的 T2D 总体影响是通过血管对脑蛋白改变进行有意调节。通过外周给药过度表达 miRNA。