Brain protein alteration by vascular overexpressed miRNA (BravomiR)

意义：阿尔茨海默病(AD)是与年龄相关的痴呆的最常见形式，影响超过5.8 百万美国人。糖尿病影响着3400万美国人(其中90%-95%是2型糖尿病，T2D)，其中 上一年有150万人新确诊。这些新病例大多是45岁的，也是 对AD前期病因学很重要。约有8800万人患有糖尿病前期。由于共病在人类中很常见，因此 对阿尔茨海默病和糖尿病的综合研究将产生重大的翻译影响。我们的目标是推出特定的共享 AD/T2D调控通路对于共病的“共治”奠定基础具有重要意义 原理：了解T2D-AD轴的共同调节将有利于两个广泛相互关联的 慢性疾病。AD神经病理学主要包括淀粉样蛋白-β(A-β)多肽的神经炎性斑块、神经- 过度磷酸化tau纤维缠结(τ)、神经炎症和突触丢失。高血糖增加 一部β的作品。其他通过T2D和AD进行操作的途径包括大脑胰岛素抵抗，以及 糖尿病引发的炎症和氧化应激升高，加剧了Aβ和tau的聚集。是这样的 共同的动态平衡失调意味着共同的调节失调。其中一个不受监管的途径就是microRNAs。 (MiRNA)，一种小的非编码RNA，调节蛋白质从mRNA的翻译。 假设：两个在T2D(miR146a，miR200b)中调节失调的特定miRNA物种也是 AD中的调节失调，以及与AD相关的重大即时和下游影响伴随着这种共同- 监管失调。方法：结合非遗传性T2D动物模型，有针对性的(人神经元和人类 神经血管)培养操作，以及人类AD样本(和对照大脑)。 目的1：验证中枢神经系统蛋白质水平的T2D中断是由血管表达的 MiR200b/miR146a。我们将测试对小鼠大脑蛋白质水平的破坏，并通过miR146a和200b进行拯救。 目的2：验证所选择的miRNAs与AD相关mRNAs的3‘-UTRs直接相互作用的假设。我们 将表征miR146a和200b对AD相关蛋白的影响，并表明miR200b和146a的活性 在小鼠模型中，当用人miR200b和/或146a处理时，在人类起源的细胞中也有对应的细胞。 目的3：验证T2D和AD类似地干扰人脑中选定的miRNAs的假设。我们会 确定miR200b和-146在T2D、AD和T2D+AD尸检脑样本中的扰动程度。 影响和未来计划：我们将在所有阶段发现和操纵共享的miRNA失调网络 对于T2D/AD，允许并行地了解早期疾病阶段的调节进展。我们将研究神经学- 在miRNA过表达/AD交叉转基因模型中的病理变化以及在AD TG模型中诱导的T2D。我们会 设计实验来跟踪T2D和AD以及没有T2D的T2D的共享生化进展 进展到公元后。总体影响是通过血管发展对大脑蛋白质变化的有意调节。 通过外周给药过表达miRNA。

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.