Function of reactive astrocytes in aging and neurodegenerative disease

反应性星形胶质细胞在衰老和神经退行性疾病中的功能

基本信息

  • 批准号:
    10476015
  • 负责人:
  • 金额:
    $ 8.28万
  • 依托单位:
  • 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:
    2020-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Reactive astrocytes (RAs) are a feature of normal aging and neurodegeneration of varying etiologies, suggesting a potential common mechanism. However, the role of RAs in neurodegeneration is complex because they can be triggered by many different stimuli and can have both beneficial and harmful effects to the Central Nervous System (CNS). Thus, a better understanding of the causes and functions of different reactive astrocytes is necessary to design therapeutics that can selectively bolster protective functions and inhibit toxic effects. There is also a vital need to expand the tools available to generate reactive astrocytes and to describe diverse reactive astrocyte functions. The long-term research goal of this application is to gain deep mechanistic understanding of the factors that elicit reactive astrocytes and the functions of different types of reactive astrocytes. For the K00 phase, the formation and the role of RAs in Alzheimer’s Disease (AD) and aging will be interrogated in the lab of Dr. Mel Feany. Dramatic changes in the extracellular matrix (ECM) and brain stiffness are observed in various CNS injuries, including Alzheimer’s disease (AD), cancer, and aging. However, while growing astrocytes on stiff substrates is known to promote a reactive astrocyte phenotype, the physiological effects of mechanically activated astrocytes have not been explored. In Aim 1, a novel model will be developed to study RAs by culturing iPSCastrocytes on substrates of different stiffness to understand the effects of mechanical changes on astrocytes. This model will be utilized to examine potential mechanisms of RA-induced toxicity. Proteoglycans (PGs) are among the most highly upregulated genes in aging and RAs. Preliminary data from Dr. Feany’s lab identified genetic interactions between PGs and models of neurodegeneration in the fly. I hypothesize that RAs produce an imbalance of PGs in the ECM, which creates an environment that is neurotoxic and inhibitory to neuronal growth and remodeling. To test this, candidate PGs will be knocked out in iPSCs, which will be differentiated to reactive and non-reactive astrocytes and co-cultured with neurons to determine the role of each PG in astrocyte-mediated neurotoxicity. Proteomics will be performed on wild-type reactive and non-reactive iPSC-astrocytes to define the reactive astrocyte secretome of mechanically activated astrocytes and identify new candidate genes. In Aim 2, in vivo fly models will be used to examine the role of PGs in toxicity of RAs in the contexts of aging and neurodegeneration. To model aging, PG candidates will be selectively knocked down in wild-type flies, which will be aged up to 2 months. Additionally, a dual bipartite expression system will be used to selectively knockdown PG candidates in glial cells while manipulating neuronal cells independently to model AD. Neurodegeneration will be assessed upon PG knockdown to determine the role of PGs in each context. The proposed studies will reveal new functions of reactive astrocytes with the ultimate goal of inspiring innovative astrocyte-targeted interventions that can be used to improve the health and well-being of the aging population. The research plan will equip the applicant with training in the fields of glia, aging and neurodegeneration.
反应性星形胶质细胞(RA)是不同病因的正常衰老和神经退行性变的特征,提示了潜在的共同机制。然而,RA在神经退行性变中的作用是复杂的,因为它们可以由许多不同的刺激触发,并且可以对中枢神经系统(CNS)具有有益和有害的影响。因此,更好地了解不同反应性星形胶质细胞的原因和功能对于设计可以选择性地增强保护功能并抑制毒性作用的治疗方法是必要的。也有一个至关重要的需要,以扩大可用的工具,以产生反应性星形胶质细胞和描述不同的反应性星形胶质细胞的功能。本申请的长期研究目标是深入了解引发反应性星形胶质细胞的因素以及不同类型反应性星形胶质细胞的功能。对于K 00阶段,RA在阿尔茨海默病(AD)和衰老中的形成和作用将在Mel Feany博士的实验室中进行研究。在各种CNS损伤中观察到细胞外基质(ECM)和脑硬度的急剧变化,包括阿尔茨海默病(AD)、癌症和衰老。然而,虽然已知在硬基质上生长星形胶质细胞可促进反应性星形胶质细胞表型,但尚未探索机械活化星形胶质细胞的生理效应。在目标1中,将开发一种新的模型来研究RA,通过在不同刚度的基质上培养iPS星形胶质细胞来了解机械变化对星形胶质细胞的影响。该模型将用于检查RA诱导毒性的潜在机制。蛋白聚糖(PG)是衰老和RA中最高度上调的基因之一。来自Feany博士实验室的初步数据确定了果蝇中PG和神经变性模型之间的遗传相互作用。我假设RA在ECM中产生PGs的不平衡,这创造了一个对神经元生长和重塑具有神经毒性和抑制作用的环境。为了测试这一点,候选PG将在iPSC中被敲除,iPSC将分化为反应性和非反应性星形胶质细胞,并与神经元共培养,以确定每种PG在星形胶质细胞介导的神经毒性中的作用。将对野生型反应性和非反应性iPSC-星形胶质细胞进行蛋白质组学研究,以确定机械活化星形胶质细胞的反应性星形胶质细胞分泌组并鉴定新的候选基因。在目标2中,将使用体内苍蝇模型来检查PG在衰老和神经退行性变背景下在RA毒性中的作用。为了模拟老化,将在野生型果蝇中选择性地敲除PG候选物,其将老化至2个月。此外,双二分表达系统将用于选择性地敲低神经胶质细胞中的PG候选物,同时独立地操纵神经元细胞以模拟AD。将在PG敲低后评估神经变性,以确定PG在每种情况下的作用。拟议的研究将揭示反应性星形胶质细胞的新功能,最终目标是激发创新的星形胶质细胞靶向干预措施,可用于改善老龄人口的健康和福祉。该研究计划将为申请人提供神经胶质,衰老和神经变性领域的培训。

项目成果

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Rachel Battaglia其他文献

Rachel Battaglia的其他文献

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{{ truncateString('Rachel Battaglia', 18)}}的其他基金

Function of reactive astrocytes in aging and neurodegenerative disease
反应性星形胶质细胞在衰老和神经退行性疾病中的功能
  • 批准号:
    10045701
  • 财政年份:
    2020
  • 资助金额:
    $ 8.28万
  • 项目类别:
Function of reactive astrocytes in aging and neurodegenerative disease
反应性星形胶质细胞在衰老和神经退行性疾病中的功能
  • 批准号:
    10689121
  • 财政年份:
    2020
  • 资助金额:
    $ 8.28万
  • 项目类别:
Function of reactive astrocytes in aging and neurodegenerative disease
反应性星形胶质细胞在衰老和神经退行性疾病中的功能
  • 批准号:
    10480931
  • 财政年份:
    2020
  • 资助金额:
    $ 8.28万
  • 项目类别:
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