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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.

项目摘要自噬是细胞降解和回收蛋白质和细胞器的过程。自噬的缺陷在于 AD，并促进自噬减轻AD模型中AD相关的组织病理学。在AD中，原因和干扰自噬的后果还没有完全理解，我们现在提出的工作将理想地填补这一知识空白。具体地说，由视黄酸基因8（STRA 8）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STRA 8功能作为一个自噬抑制因子。因此，Stra 8敲除激活自噬。基于此，我们的R 01-HD 103888 研究STRA 8介导的生殖细胞发育和减数分裂中的自噬抑制。在我们的研究中，我们发现STRA 8出乎意料地在小鼠脑细胞中表达。在功能上，我们的数据显示Stra 8-KO小鼠在他们的大脑中表现出增加的自噬，表明STRA 8作为自噬抑制剂的作用是在生殖细胞和脑细胞中都是保守的重要的是，在老年小鼠大脑中，我们发现STRA 8表现出纺锤形堆积此外，我们的数据表明，在尸检中，来自年龄匹配的人AD与非AD脑的样品，并且检测到STRA 8蛋白积累在人类AD大脑中。这些观察结果将STRA 8与AD联系起来，无论是作为一种蛋白质，其生物学变化的一部分，或作为一种蛋白质，有助于蛋白质稳态的恶化， AD.由于STRA 8起到抑制自噬的作用，因此STRA 8水平在衰老期间和AD脑中增加，并且AD 大脑表现出有缺陷的自噬和蛋白质应激，任何一种情况都可能扰乱神经元的完整性。这行政补充父R 01-HD 103888赠款将扩大我们的研究STRA 8介导的自噬抑制从生殖细胞发育和发展的新焦点AD发病机制。我们有一种假说认为，通过抑制自噬，上调的STRA 8表达可以改变AD组织学改变，神经功能障碍，神经退行性变，和行为在转基因AD小鼠模型。目标1：将研究Stra 8缺失是否改善5XFAD小鼠中AD的生化和行为标志。在目标2中，我们将确定异位STRA 8过表达是否诱导蛋白质稳态失调和神经元凋亡。在5XFAD小鼠中，AD的发病机制恶化。获得的知识将告知 STRA 8在AD发病机制中的潜在新作用，并解决STRA 8是否可以作为一种新的AD 治疗靶点此外，文献声称AD神经元重新进入细胞周期。STRA 8的作用发育可能告知AD的这一方面，并作为异常细胞周期和扰乱了自噬