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.

项目摘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并促进自噬可减轻AD模型中与AD相关的组织病理学。在广告中，原因和扰动自噬的后果并不完全理解，我们现在提出的工作理想情况下将解决此知识差距。具体而言，由视黄酸基因8（Stra8）刺激的最初被描述为减数分裂起始需要的生殖细胞特异性蛋白质。我们是第一个报告stra8函数的人自噬的抑制剂。因此，Stra8敲除激活自噬。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的抑制。在我们的学习期间，我们发现Stra8在小鼠脑细胞中意外表达。在功能上，我们的数据显示Stra8-KO小鼠暴露于大脑中自噬增加了，表明Stra8作为自噬的抑制剂的作用是在种系和脑细胞中保守。重要的是，在老年小鼠大脑中，我们发现Stra8展示主轴形积累。此外，我们的数据表明，尸检中Stra8 mRNA的表达升高来自年龄匹配的人类广告与非AD大脑的样品，并检测到Stra8蛋白的积累在人类的大脑中。这些观察结果将Stra8与AD联系起来，要么是一种蛋白质，其生物学会变化为一部分 AD中的补偿性反应或作为有助于蛋白质稳态定义的蛋白质的蛋白质广告。随着Stra8的作用以抑制自噬，在衰老和广告大脑中，Stra8的水平会增加，并且AD 大脑暴露有缺陷的自噬和蛋白质应激，这两种情况都可能使神经元完整性呈现。这父母R01-HD103888赠款的行政补充将扩展我们对Stra8介导的研究生殖细胞发育中的自噬抑制并在AD发病机理中发展出新的重点。我们的假设是，通过自噬的表达，更新的Stra8表达可以修改AD组织学转基因AD小鼠模型中的变化，神经功能功能，神经变性和行为。在AIM 1中，我们将研究Stra8缺失是否改善了5XFAD小鼠AD的生化和行为标志。在AIM 2中，我们将确定异位stra8过表达是否诱导蛋白质dyshomeostasis和Neuron 正常小鼠的损失和加剧5xFAD小鼠的AD发病机理。获得的知识将告知 Stra8在AD发病机理中的潜在新作用，并解决Stra8是否可以用作新的广告治疗靶标。此外，文献声称AD神经元重新进入细胞周期。 Stra8的角色开发可能会为AD的这一方面提供信息，并用作异常细胞循环之间的分子桥扰动自噬。