Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology

GWAS 危险因子 BIN1 在阿尔茨海默病神经病理学中的细胞自主和非细胞自主作用

基本信息

  • 批准号:
    10176956
  • 负责人:
  • 金额:
    $ 87.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-08-15 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY This proposal focuses on BIN1, one of the recently identified common risk genes within the major susceptibility loci for late-onset Alzheimer's disease (LOAD) (second only to APOE). BIN1 (Bridging INtegrator-1) is a member of a family of adaptor proteins that regulate membrane dynamics in the context of endocytosis and membrane remodeling. Alternate splicing of the 20 exons in BIN1 gene generates ubiquitous and tissue- specific isoforms, which differ in their tissue distribution, subcellular localization, and function. These functions include cell cycle progression, apoptosis, cytoskeletal organization, and DNA repair. An increase of BIN1 expression and alternate splicing of BIN1 have been reported in the brains of individuals with LOAD but how these observations translate to increased risk for AD is entirely not clear. In preliminary studies, we have characterized prominent BIN1 expression in mature oligodendrocytes in the gray and white matter in rodent and the human brain. By generating oligodendrocyte-specific Bin1 conditional knock out (cKO) mice, we confirmed that BIN1 is mainly expressed in mature oligodendrocytes. Interestingly, we observe aberrant BIN1 expression near human senile plaques and BIN1 accrual in amyloid deposits of AD transgenic mouse models. Based on these novel findings, we hypothesize that BIN1 functions in mature oligodendrocytes, and that alteration in BIN1 expression and/or function in oligodendrocytes plays a role in AD-related pathogenic processes and neurodegeneration in a non-cell autonomous manner. We propose the following specific aims to test novel hypothesis related to the role of BIN1 in AD. The Specific Aims of this proposal are: Aim 1: To test the hypothesis that BIN1 cellular expression and localization are altered in AD brain. We will investigate the BIN1 expression and alternate splicing in normal and diseased human brain. We will determine the subcellular localization of BIN1 by fractionation and confocal microscopy, and clarify the ultrastructural BIN1 localization using immunoelectron microscopy. Aim 2: To test the hypothesis that downregulation of BIN1 expression will attenuate amyloid and tau pathology in transgenic mice. We will ascertain whether cell-type specific loss of BIN1 expression in neurons or mature oligodendrocytes will attenuate AD-related neuropathology and behavior deficits in transgenic AD mouse models. Aim 3: To test the hypothesis that BIN1 plays a role in oligodendrocyte differentiation, survival, and maturation, as well as myelination in vivo. We will utilize Bin1 cKO mouse models and cultured oligodendrocytes to test this hypothesis. This proposal is timely, unique, and highly innovative. We believe that our investigation will uncover significant insights on BIN1's function in the brain, characterize novel Bin1 cKO mouse models of interest to the AD field, establish whether attenuation of BIN1 expression provides a novel strategy for disease intervention, and lay the foundation for characterization of BIN1 functional variants linked to AD, and guide future functional characterization of biological pathways and pathogenic mechanisms regulated by this major LOAD risk gene.
项目总结

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β-amyloid-toxicity.
  • DOI:
    10.1111/nan.12647
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Wang Y;Wu Q;Anand BG;Karthivashan G;Phukan G;Yang J;Thinakaran G;Westaway D;Kar S
  • 通讯作者:
    Kar S
Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.
前脑 BIN1 的缺失会减轻 tau 蛋白病模型中的海马病理学和神经炎症。
  • DOI:
    10.1093/brain/awac318
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ponnusamy,Moorthi;Wang,Shuai;Yuksel,Melike;Hansen,MitchellT;Blazier,DanielleM;McMillan,JosephD;Zhang,Xiaolin;Dammer,EricB;Collier,Lisa;Thinakaran,Gopal
  • 通讯作者:
    Thinakaran,Gopal
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

GOPAL THINAKARAN其他文献

GOPAL THINAKARAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('GOPAL THINAKARAN', 18)}}的其他基金

The role of Alzheimer's disease GWAS risk factor BIN1 in tau neuropathology and propagation in vivo
阿尔茨海默病 GWAS 危险因子 BIN1 在 tau 神经病理学和体内传播中的作用
  • 批准号:
    10448676
  • 财政年份:
    2022
  • 资助金额:
    $ 87.59万
  • 项目类别:
High-plex Protein and Gene Expression Digital Spatial Profiler for Core Facility
用于核心设施的高复杂蛋白质和基因表达数字空间分析仪
  • 批准号:
    10177265
  • 财政年份:
    2021
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology
GWAS 危险因子 BIN1 在阿尔茨海默病神经病理学中的细胞自主和非细胞自主作用
  • 批准号:
    9198396
  • 财政年份:
    2016
  • 资助金额:
    $ 87.59万
  • 项目类别:
Regulation of BACE1 transcytosis in hippocampal neurons
海马神经元 BACE1 转胞吞作用的调节
  • 批准号:
    9125717
  • 财政年份:
    2015
  • 资助金额:
    $ 87.59万
  • 项目类别:
Multi-purpose Superresolution Microscope for Core Facility
用于核心设施的多用途超分辨率显微镜
  • 批准号:
    8246831
  • 财政年份:
    2012
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    7919038
  • 财政年份:
    2009
  • 资助金额:
    $ 87.59万
  • 项目类别:
Mouse model for neuroprotection
神经保护小鼠模型
  • 批准号:
    7019332
  • 财政年份:
    2006
  • 资助金额:
    $ 87.59万
  • 项目类别:
Mouse model for neuroprotection
神经保护小鼠模型
  • 批准号:
    7229860
  • 财政年份:
    2006
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    6559483
  • 财政年份:
    2002
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    6755908
  • 财政年份:
    2002
  • 资助金额:
    $ 87.59万
  • 项目类别:

相似海外基金

Mechanisms of Cellular Senescence Driving Intervertebral Disc Aging through Local Cell Autonomous and Systemic Non-Cell Autonomous Processes
细胞衰老通过局部细胞自主和全身非细胞自主过程驱动椎间盘老化的机制
  • 批准号:
    10635092
  • 财政年份:
    2023
  • 资助金额:
    $ 87.59万
  • 项目类别:
Non-cell autonomous consequences of cytoplasmic DNA
细胞质 DNA 的非细胞自主后果
  • 批准号:
    10748962
  • 财政年份:
    2023
  • 资助金额:
    $ 87.59万
  • 项目类别:
Identifying cell type-specific autonomous and non-autonomous interactions in AD
识别 AD 中细胞类型特异性的自主和非自主相互作用
  • 批准号:
    10446168
  • 财政年份:
    2022
  • 资助金额:
    $ 87.59万
  • 项目类别:
Modulation of non-cell-autonomous signalling mechanisms in iPS cell generation
iPS 细胞生成过程中非细胞自主信号机制的调节
  • 批准号:
    2753937
  • 财政年份:
    2022
  • 资助金额:
    $ 87.59万
  • 项目类别:
    Studentship
Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias
阿尔茨海默病和相关痴呆的细胞自主和非自主机制
  • 批准号:
    10491094
  • 财政年份:
    2021
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias
阿尔茨海默病和相关痴呆的细胞自主和非自主机制
  • 批准号:
    10647782
  • 财政年份:
    2021
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias
阿尔茨海默病和相关痴呆的细胞自主和非自主机制
  • 批准号:
    10187414
  • 财政年份:
    2021
  • 资助金额:
    $ 87.59万
  • 项目类别:
Cell Non-Autonomous Regulation of NeuronalProteostasis
神经元蛋白质稳态的细胞非自主调节
  • 批准号:
    10359732
  • 财政年份:
    2020
  • 资助金额:
    $ 87.59万
  • 项目类别:
Novel role of Golgi apparatus for non-cell autonomous events
高尔基体在非细胞自主事件中的新作用
  • 批准号:
    20H00467
  • 财政年份:
    2020
  • 资助金额:
    $ 87.59万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Non-cell autonomous signaling modes of retinoic acid
视黄酸的非细胞自主信号传导模式
  • 批准号:
    549947-2020
  • 财政年份:
    2020
  • 资助金额:
    $ 87.59万
  • 项目类别:
    University Undergraduate Student Research Awards
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了