miR-29: A brain homeostasis molecule for Alzheimer’s disease prevention

miR-29:一种用于预防阿尔茨海默病的大脑稳态分子

基本信息

  • 批准号:
    10667151
  • 负责人:
  • 金额:
    $ 62.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary One of the underexplored aspects of neuronal biology is that as postmitotic neurons become mature, they undergo dynamic changes to ensure that the mature nervous system is capable of long-term survival and function. Understanding these mechanisms that are critical for the long-term homeostasis of the adult brain is important as their dysfunction could increase the vulnerability of neurons to age-related neurodegeneration, such as Alzheimer’s disease (AD). We have identified miR-29 as a microRNA that is strikingly induced during brain maturation. In contrast to the high miR-29 levels that are maintained in the normal adult brains, miR-29 levels are reduced in Alzheimer’s Disease patients. miR-29 is recognized to target many of the genes in the AD pathways including BACE1, NAV3, and IFITM3. To evaluate the functional importance of miR-29, we generated mice in which miR-29 can be conditionally deleted. Mice deficient for miR-29 in the brain are born normal but then progressively decline, exhibiting neurological defects and early lethality. These results show that miR-29 is physiologically important for the maintenance of long-term homeostasis in the adult brain. Reduction in miR-29 levels could therefore increase the vulnerability of mature neurons to become dysfunctional in the context of AD. We have recently generated mice in which miR-29 levels can be conditionally reduced in the adult brain. Thus, the overall focus of our proposal is to define the consequences of miR-29 reduction in the adult brain and to evaluate the therapeutic potential of miR-29 for AD. Specifically, in Aim 1, we will conduct single-cell RNA- seq analysis to identify the specific cell types that are most impacted by miR-29 reduction in the adult brain. We will also examine if miR-29 reduction causes changes in dendritic spine morphology and neuronal arborization in the adult brain. Our results have revealed that an essential function of miR-29 is to regulate non-canonical (non-CG), CH methylation in the mature brain via its targeting of the methyltransferase Dnmt3a, where the loss of miR-29 results in CH hypermethylation and reprogramming of gene expression. In Aim 2, we will examine if CH hypermethylation is a common feature of AD in three distinct mouse models of AD and AD patient brain samples. Our hypothesis is that restoring miR-29 levels would have therapeutic benefit for AD. Thus, in Aim 3, we will examine whether AAV-mediated delivery of miR-29 confers benefit in human stem cell and preclinical mouse models of AD. Overall, we are excited to be working on a molecule, miR-29, that has a unique and essential function in the mature brain. Our studies will help define its mechanisms of action as well as evaluate its therapeutic potential in the context of Alzheimer’s Disease.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Mohanish P Deshmukh其他文献

Mohanish P Deshmukh的其他文献

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{{ truncateString('Mohanish P Deshmukh', 18)}}的其他基金

Unexpected Function of Inflammasomes in Axon Pruning: Focus on NLRP1
炎症小体在轴突修剪中的意外功能:聚焦 NLRP1
  • 批准号:
    10156766
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
  • 批准号:
    10596657
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Exploring Apoptosome-Independent Mechanisms for Casp9 activation in Axon Pruning
探索轴突修剪中 Casp9 激活的独立凋亡体机制
  • 批准号:
    10288453
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
  • 批准号:
    10417219
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Essential Function of miR-29 in the Mature Brain
miR-29 在成熟大脑中的基本功能
  • 批准号:
    9904306
  • 财政年份:
    2017
  • 资助金额:
    $ 62.28万
  • 项目类别:
Establishing Apoptotic Thresholds: Insights from Neurons and Stem Cells to Cancer
建立细胞凋亡阈值:从神经元和干细胞对癌症的见解
  • 批准号:
    9281085
  • 财政年份:
    2016
  • 资助金额:
    $ 62.28万
  • 项目类别:
Establishing Apoptotic Thresholds: Insights from Neurons and Stem Cells to Cancer
建立细胞凋亡阈值:从神经元和干细胞对癌症的见解
  • 批准号:
    9351806
  • 财政年份:
    2016
  • 资助金额:
    $ 62.28万
  • 项目类别:
Establishing Apoptotic Thresholds: Insights from Neurons and Stem Cells to Cancer
建立细胞凋亡阈值:从神经元和干细胞对癌症的见解
  • 批准号:
    9079061
  • 财政年份:
    2016
  • 资助金额:
    $ 62.28万
  • 项目类别:
Focus on Dicer inhibition as a novel treatment for brain tumors
专注于 Dicer 抑制作为脑肿瘤的新型治疗方法
  • 批准号:
    9149075
  • 财政年份:
    2015
  • 资助金额:
    $ 62.28万
  • 项目类别:
Focus on Dicer inhibition as a novel treatment for brain tumors
专注于 Dicer 抑制作为脑肿瘤的新型治疗方法
  • 批准号:
    9056040
  • 财政年份:
    2015
  • 资助金额:
    $ 62.28万
  • 项目类别:

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