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Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

通过自噬途径定义减数分裂起始机制

基本信息

批准号：
10711993
负责人：
Ning Wang
金额：
$ 32.66万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711993
关键词：
AD transgenic mice Acceleration Address Administrative Supplement Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Attenuated Autophagocytosis Autopsy Behavior Behavioral Biochemical Biology Brain Cell Cycle Cells Cognition Collaborations DNA Double Strand Break Data Deposition Deterioration Development Doxycycline Elements Exhibits Genes Germ Cells Grant Heat shock proteins Hippocampus Histology Histopathology Human Impaired cognition Knock-in Mouse Knock-out Knockout Mice Knowledge Link Literature LoxP-flanked allele Mediating Meiosis Meiotic Recombination Molecular Mus Nerve Degeneration Neurons Organelles Parents Pathogenesis Pathology Pathway interactions Process Proteins Recycling Reporting Repression Research Role Sampling Senile Plaques Shapes Testing Tetracyclines Transgenic Mice Tretinoin Work aged brain cell cell type cognitive function conditional knockout dentate gyrus improved inhibition of autophagy learning strategy mRNA Expression morris water maze mouse model nestin protein neuron loss novel overexpression proteostasis response single-cell RNA sequencing therapeutic target tool transgenic model of alzheimer disease

项目摘要

PROJECT SUMMARY Autophagy is the process by which cells degrade and recycle proteins and organelles. Autophagy is defective in AD, and promoting autophagy mitigates AD-associated histopathology in AD models. In AD, the causes and consequences of perturbed autophagy are not entirely understood and the work we now propose will ideally address this knowledge gap. Specifically, stimulated by retinoic acid gene 8 (STRA8) was initially described as a germ cell-specific protein required for meiotic initiation. We are the first to report STRA8 functions as a suppressor of autophagy. As such, Stra8 knockout activates autophagy. Based on this, our R01-HD103888 studies STRA8-mediated suppression of autophagy in germ cell development and meiosis. During our studies, we found STRA8 is unexpectedly expressed in mouse brain cells. Functionally, our data show Stra8-KO mice exhibit increased autophagy in their brains, indicating that the role of STRA8 as a suppressor of autophagy is conserved in both germline and brain cells. Importantly, in aged mouse brains, we found that STRA8 exhibits spindle-shaped accumulation. Moreover, our data show that STRA8 mRNA expression is elevated in autopsied samples from age-matched human AD versus non-AD brains and that STRA8 protein accumulation is detected in human AD brains. These observations link STRA8 to AD, either as a protein whose biology changes as part of a compensatory response in AD or as a protein that contributes to the deterioration of protein homeostasis in AD. As STRA8 acts to suppress autophagy, STRA8 levels increase during aging and in AD brains, and AD brains exhibit defective autophagy and protein stress, either scenario likely perturbs neuronal integrity. This Administrative Supplement to the parent R01-HD103888 grant will extend our studies of STRA8-mediated autophagy suppression from germ cell development and develop a new focus in AD pathogenesis. Our hypothesis is that upregulated STRA8 expression, through its repression of autophagy, can modify AD histology changes, neurodysfunction, neurodegeneration, and behavior in a transgenic AD mouse model. In Aim 1, we will investigate whether Stra8 deletion improves the biochemical and behavioral hallmarks of AD in 5XFAD mice. In Aim 2, we will determine whether ectopic STRA8 overexpression induces protein dyshomeostasis and neuron loss in normal mice and exacerbates AD pathogenesis in 5XFAD mice. Knowledge obtained will inform a potential novel role for STRA8 in AD pathogenesis and address whether STRA8 could serve as a novel AD therapeutic target. Moreover, the literature claims AD neurons re-enter the cell cycle. STRA8’s role in development may inform this aspect of AD and serve as a molecular bridge between aberrant cell cycling and perturbed autophagy.

项目概要自噬是细胞降解和回收蛋白质和细胞器的过程。自噬有缺陷 AD 和促进自噬可减轻 AD 模型中与 AD 相关的组织病理学。在 AD 中，原因和自噬受到干扰的后果尚未完全了解，我们现在提出的工作理想情况下将解决这一知识差距。具体来说，由视黄酸基因 8 (STRA8) 刺激最初被描述为减数分裂起始所需的生殖细胞特异性蛋白质。我们是第一个报告 STRA8 功能的人自噬抑制剂。因此，Stra8 敲除会激活自噬。基于此，我们的R01-HD103888 研究 STRA8 介导的生殖细胞发育和减数分裂中自噬抑制。在我们学习期间，我们发现STRA8在小鼠脑细胞中出人意料地表达。从功能上来说，我们的数据显示 Stra8-KO 小鼠在他们的大脑中表现出增加的自噬，表明 STRA8 作为自噬抑制剂的作用是在生殖细胞和脑细胞中均保守。重要的是，在老年小鼠大脑中，我们发现 STRA8 表现出纺锤状堆积。此外，我们的数据表明，尸检中 STRA8 mRNA 表达升高来自年龄匹配的人类 AD 与非 AD 大脑的样本，并且检测到 STRA8 蛋白积累在人类 AD 大脑中。这些观察结果将 STRA8 与 AD 联系起来，要么作为一种蛋白质，其生物学变化作为其一部分 AD 中的代偿反应或作为导致蛋白质稳态恶化的蛋白质广告。由于 STRA8 具有抑制自噬的作用，因此 STRA8 水平在衰老过程中以及 AD 大脑中会增加，而 AD 大脑表现出有缺陷的自噬和蛋白质应激，这两种情况都可能扰乱神经元的完整性。这对父 R01-HD103888 拨款的行政补充将扩大我们对 STRA8 介导的研究生殖细胞发育中的自噬抑制并成为 AD 发病机制的新焦点。我们的假设上调的 STRA8 表达通过抑制自噬可以改变 AD 组织学转基因 AD 小鼠模型中的变化、神经功能障碍、神经变性和行为。在目标 1 中，我们将研究 Stra8 缺失是否改善 5XFAD 小鼠 AD 的生化和行为特征。在目标 2 中，我们将确定异位 STRA8 过表达是否会诱导蛋白质稳态失衡和神经元正常小鼠的损失并加剧 5XFAD 小鼠的 AD 发病机制。获得的知识将告知 STRA8 在 AD 发病机制中的潜在新作用，并探讨 STRA8 是否可以作为一种新型 AD 治疗目标。此外，文献声称 AD 神经元重新进入细胞周期。 STRA8 的作用发育可能会告知 AD 的这一方面，并充当异常细胞周期和异常细胞之间的分子桥梁。自噬受到干扰。