Elucidating the role of placental growth factor in diffuse white matter disease

阐明胎盘生长因子在弥漫性白质疾病中的作用

基本信息

  • 批准号:
    10379950
  • 负责人:
  • 金额:
    $ 69.78万
  • 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:
    2020-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Abstract Diffuse white matter disease (DWD) is a common manifestation of small-vessel cerebrovascular pathology and a key subtype of vascular contributions to cognitive impairment and dementia (VCID). However, the mechanistic underpinnings of DWD remain incompletely characterized. Based on assessment of extensive data in humans and animal models, we have identified angiogenic mediators, in particular placental growth factor (PlGF), as being strongly associated with diffuse white matter disease. Much like the pathologic angiogenesis that occurs in retinopathies, pathologic angiogenesis in the brain results in blood-brain barrier leakage and, counterintuitively, tissue ischemia. We have exciting preliminary data indicating robust relationships between PlGF and human DWD. We have also identified PlGF as being increased in association with blood-brain barrier leakage. We hypothesize that PlGF, and related angiogenic mediators, result in pathologic angiogenesis, with leaky, tortuous vessels and surrounding inflammation, leading to diffuse white matter disease. Importantly, these pathologic changes also represent a potentially targetable mechanism to improve cognition in aging. To test these hypotheses, we propose focused studies in an extensively characterized human cohort, and a mouse model of small vessel disease. We answer the “what, where, why” questions surrounding PlGF. “What” cell type is responsible for PlGF; “where” is PlGF being expressed; “why” is PlGF upregulated and can it be modulated. To test these hypotheses, we propose focused studies in an extensively characterized human autopsy cohort, and a mouse model of small vessel disease: Specific Aim 1: Determine contributions to plasma PLGF, and related angiogenic proteins, using cell- specific exosomes and their association with periventricular and deep white matter pathologies. Specific Aim 2: Ascertain the regional expression of PLGF, and related angiogenic proteins, within, adjacent to, and distant from, periventricular and DWD and the association with aberrant angiogenesis. Specific Aim 3: Test the potential to manipulate PLGF related small vessel pathology in response to hyperhomocysteinemia (HHcy)-induced small vessel disease.
摘要

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Donna M Wilcock其他文献

Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage
  • DOI:
    10.1186/1742-2094-1-24
  • 发表时间:
    2004-01-01
  • 期刊:
  • 影响因子:
    10.100
  • 作者:
    Donna M Wilcock;Amyn Rojiani;Arnon Rosenthal;Sangeetha Subbarao;Melissa J Freeman;Marcia N Gordon;Dave Morgan
  • 通讯作者:
    Dave Morgan

Donna M Wilcock的其他文献

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{{ truncateString('Donna M Wilcock', 18)}}的其他基金

Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
  • 批准号:
    10851244
  • 财政年份:
    2023
  • 资助金额:
    $ 69.78万
  • 项目类别:
Establishing the role of MMP9 in amyloid-immunotherapy-induced ARIA
确定 MMP9 在淀粉样蛋白免疫疗法诱导的 ARIA 中的作用
  • 批准号:
    10607620
  • 财政年份:
    2022
  • 资助金额:
    $ 69.78万
  • 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
  • 批准号:
    10261967
  • 财政年份:
    2021
  • 资助金额:
    $ 69.78万
  • 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
  • 批准号:
    10459471
  • 财政年份:
    2021
  • 资助金额:
    $ 69.78万
  • 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
  • 批准号:
    10662361
  • 财政年份:
    2021
  • 资助金额:
    $ 69.78万
  • 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
  • 批准号:
    10133181
  • 财政年份:
    2020
  • 资助金额:
    $ 69.78万
  • 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
  • 批准号:
    10597648
  • 财政年份:
    2020
  • 资助金额:
    $ 69.78万
  • 项目类别:
Therapeutic targeting of TREM2 for Alzheimer's disease
TREM2 治疗阿尔茨海默病的靶向治疗
  • 批准号:
    9423846
  • 财政年份:
    2018
  • 资助金额:
    $ 69.78万
  • 项目类别:
Neurovascular astrocyte dysfunction in VCID
VCID 中的神经血管星形胶质细胞功能障碍
  • 批准号:
    9306465
  • 财政年份:
    2017
  • 资助金额:
    $ 69.78万
  • 项目类别:
Neurovascular astrocyte dysfunction in VCID
VCID 中的神经血管星形胶质细胞功能障碍
  • 批准号:
    10183340
  • 财政年份:
    2017
  • 资助金额:
    $ 69.78万
  • 项目类别:

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