Characterizing Vulnerable Cell Types in C9orf72-FTD

表征 C9orf72-FTD 中的脆弱细胞类型

基本信息

  • 批准号:
    10464266
  • 负责人:
  • 金额:
    $ 5.18万
  • 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:
    2023-01-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract C9orf72 expansion mutations are the most common genetic cause of frontotemporal dementia (C9-FTD), a fatal and incurable neurodegenerative disease. C9-FTD is most commonly neuropathologically characterized by frontotemporal lobar degeneration (C9-FTLD) and the accumulation of phospho-TDP-43 (pTDP-43) inclusions in neurons and glia. In C9-FTLD, the medial orbitofrontal cortex (mOFC) is affected early in the disease course, and individuals with mOFC lesions phenocopy patients with FTD, suggesting that mOFC dysfunction impacts FTD clinical phenotypes. In disease, the mOFC exhibits pTDP-43 inclusions, neuronal degeneration, and neuroinflammation, including the development of pathologic microglia. In other diseases, pathologic microglia increase extracellular glutamate and induce death in excitatory neurons. However, these factors’ relative contributions to C9-FTLD pathogenesis are not well understood, and the molecular profiles of degenerating neurons (termed vulnerable neurons) and pathologic microglia in the mOFC are unknown. We hypothesize that in C9-FTLD, pathologic microglia contribute to the selective degeneration of vulnerable populations of excitatory neurons, resulting in dementia. This proposal aims to use transcriptomic methods to identify vulnerable neuron and pathologic microglia subtypes and characterize their molecular profiles, spatial distributions, and interactions that may be contributing to disease progression. To this end, Aim #1 will use single-nucleus RNA sequencing to identify and characterize the pathologic microglia subtypes that arise and the vulnerable neuron subtypes that degenerate in C9-FTLD. Cellular proximity is the basis for intercellular interactions, and Aim #2 will use spatial transcriptomics to identify where these pathologic microglia and vulnerable neurons are spatially distributed as well as their spatial proximities in relation to each other and to pTDP-43 inclusions. A better understanding of how C9-FTLD changes neurons’ and microglia’s gene expression patterns, their spatial distributions, and their interactions may lead to strategies to protect cells from disease and patients from dementia. These studies will emphasize how pathologic microglia can contribute to neurodegeneration, enabling the development of microglia-targeted therapies for C9-FTD and other neurodegenerative diseases. Through this project, I will develop expertise in the use of histological and computational techniques. My sponsor, Dr. Edward Lee, is committed to my training and success as a physician-scientist.
项目总结/摘要 C9 orf 72扩展突变是额颞叶痴呆(C9-FTD)最常见的遗传原因, 致命且无法治愈的神经退行性疾病。C9-FTD最常见的神经病理学特征 通过额颞叶变性(C9-FTLD)和磷酸-TDP-43(pTDP-43)的积累, 神经元和神经胶质中的内含物。在C9-FTLD中,内侧眶额皮质(mOFC)在早期受到影响, 病程和mOFC病变个体与FTD患者表型相似,表明mOFC 功能障碍影响FTD临床表型。在疾病中,mOFC表现出pTDP-43包涵体,神经元包涵体, 变性和神经炎症,包括病理性小胶质细胞的发展。在其他疾病中, 病理性小胶质细胞增加细胞外谷氨酸并诱导兴奋性神经元死亡。但这些 因子对C9-FTLD发病机制的相对贡献尚不清楚, mOFC中的退化神经元(称为脆弱神经元)和病理性小胶质细胞是未知的。 我们假设在C9-FTLD中,病理性小胶质细胞有助于选择性变性。 易受伤害的兴奋性神经元群体,导致痴呆症。该提案旨在利用 转录组学方法来鉴定脆弱神经元和病理性小胶质细胞亚型并表征其 分子谱、空间分布和可能导致疾病进展的相互作用。到 为此,目标1将使用单核RNA测序来鉴定和表征病理性小胶质细胞 C9-FTLD中出现的脆弱神经元亚型和退化的脆弱神经元亚型。细胞接近度是 目标2将使用空间转录组学来确定这些病理性的 小胶质细胞和脆弱神经元在空间上分布以及它们之间的空间接近度 其他和pTDP-43夹杂物。 更好地了解C9-FTLD如何改变神经元和小胶质细胞的基因表达模式, 空间分布及其相互作用可能会导致保护细胞免受疾病和患者影响的策略 得了痴呆这些研究将强调病理性小胶质细胞如何导致神经变性, 从而能够开发针对C9-FTD和其他神经退行性疾病的小胶质细胞靶向疗法。 通过这个项目,我将发展组织学和计算技术的使用专业知识。我 赞助商,爱德华·李博士,致力于我的训练和成功,作为一个医生科学家。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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

{{ 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 }}

David Dai其他文献

David Dai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 }}

相似海外基金

AMFaces: Advanced Additive Manufacturing of User-Focused Facial Prostheses with Real-Life Colour Appearance
AMFaces:以用户为中心的面部假体的先进增材制造,具有真实的色彩外观
  • 批准号:
    EP/W033968/1
  • 财政年份:
    2023
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Research Grant
Understanding the appearance mechanism of ferroelectric liquid crystals showing spontaneous polarization in the director and developing their applications.
了解铁电液晶在指向矢中表现出自发极化的出现机制并开发其应用。
  • 批准号:
    23H00303
  • 财政年份:
    2023
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Elucidating the mechanism in the color appearance of small-field stimulus on chromatic surroundings
阐明彩色环境中小场刺激的颜色外观机制
  • 批准号:
    22K20317
  • 财政年份:
    2022
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
Body, appearance, and health surveillance in female youth friendship contexts
女性青少年友谊背景下的身体、外表和健康监测
  • 批准号:
    2690554
  • 财政年份:
    2022
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Studentship
Learning to Recognize Faces Despite Within-Person Variability in Appearance: A Developmental Approach
尽管人与人之间的外表存在差异,但仍要学习识别面孔:一种发展方法
  • 批准号:
    RGPIN-2022-04386
  • 财政年份:
    2022
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Discovery Grants Program - Individual
Path-space Exploration for Light Transport and Appearance Modelling
光传输和外观建模的路径空间探索
  • 批准号:
    RGPIN-2018-05669
  • 财政年份:
    2022
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Discovery Grants Program - Individual
Appearance of negative influences of global warming on crop production and measures against it
全球变暖对农作物生产的负面影响的显现及应对措施
  • 批准号:
    21H02330
  • 财政年份:
    2021
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
A sociological study on appearance discrimination during employment selection
就业选择中外表歧视的社会学研究
  • 批准号:
    21K13447
  • 财政年份:
    2021
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The influence of river environment on urban appearance of wildlife
河流环境对野生动物城市面貌的影响
  • 批准号:
    21K12322
  • 财政年份:
    2021
  • 资助金额:
    $ 5.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Method for assessing women's perceptions of their appearance in the context of breast cancer care
评估乳腺癌护理背景下女性对其外表的看法的方法
  • 批准号:
    10196213
  • 财政年份:
    2021
  • 资助金额:
    $ 5.18万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了