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:10597648
- 负责人:
- 金额:$ 10.34万
- 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 2023-07-15
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAgingAlgorithmsAngiogenic ProteinsAnimal ModelAntibodiesAstrocytesAutopsyBiochemicalBiological MarkersBlood - brain barrier anatomyBlood VesselsBrainCellsCerebrovascular systemChronicCirculationClinicalCognitionDataDementiaDiameterDietDiffuseDistantEndothelial CellsExtravasationHemorrhageHistologicHistologyHumanHuman CharacteristicsHyperhomocysteinemiaIndividualInfarctionInflammationIschemiaKentuckyKnockout MiceLengthLongitudinal cohortMagnetic Resonance ImagingMediatingMediatorMicrogliaMicrovascular DysfunctionModelingMolecularMorphologyMusNeuronsOligodendrogliaPGF genePathologicPathologic NeovascularizationPathologyPlasmaProteinsQuantitative Reverse Transcriptase PCRResearch PersonnelResourcesRetinal DiseasesRodentRoleSamplingSeriesTechniquesTestingTherapeutic InterventionTimeTissuesUniversitiesVentricularWestern BlottingWhite Matter DiseaseWild Type Mouseangiogenesiscell typecerebrovascularcerebrovascular pathologycohortdigitaldigital pathologyexosomegray matterhuman modelhuman tissueimprovedinnovationinterestintravital imagingmouse modelneuropathologyneurovascularnovelresponsetargeted treatmentvascular cognitive impairment and dementiawhite matter
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
弥漫性白质病(DWD)是小血管病变和脑血管病变的常见表现。
血管导致认知损害和痴呆(VCID)的一个关键亚型。然而,
DWD的机械基础仍未完全确定。基于对广泛的
在人类和动物模型中,我们已经确定了血管生成介质,特别是胎盘
生长因子(PlGF)与弥漫性白质疾病密切相关。
与视网膜病变中发生的病理性血管生成非常相似,大脑中的病理性血管生成
导致血脑屏障渗漏,与直觉相反,还会导致组织缺血。我们有激动人心的预赛
数据表明PlGF和人类DWD之间存在牢固的关系。我们还确认了PlGF是
与血脑屏障渗漏相关的增加。我们假设PlGF和相关的
血管生成介质,导致病理性血管生成,具有渗漏、曲折的血管及其周围
炎症,导致弥漫性白质疾病。重要的是,这些病理变化也
代表了一种潜在的有针对性的机制,可以改善衰老过程中的认知。为了检验这些假设,
我们建议在广泛表征的人类队列和小血管的小鼠模型中进行有针对性的研究。
疾病。我们回答了围绕PlGF的“什么、在哪里、为什么”的问题。“什么”细胞类型负责
PlGF;“Where”是PlGF的表达;“为什么”是PlGF上调,它能被调节吗?为了测试这些
假设,我们建议对广泛描述的人类尸检队列和一只小鼠进行有针对性的研究
小血管病变模型:
具体目标1:确定对血浆PLGF和相关血管生成蛋白的贡献,使用细胞-
特殊的外切体及其与脑室周围和深层白质病理的关系。
具体目标2:确定PLGF和相关血管生成蛋白在体内的区域表达
邻近和远离脑室周围和弥漫性血管病变及其与异常血管生成的关系。
具体目标3:测试操纵PLGF相关小血管病理反应的可能性
高同型半胱氨酸血症(HHcy)引起的小血管疾病。
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)
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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:
$ 10.34万 - 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
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10607620 - 财政年份:2022
- 资助金额:
$ 10.34万 - 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:
$ 10.34万 - 项目类别:
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核心F:肯塔基大学阿尔茨海默病核心中心
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10459471 - 财政年份:2021
- 资助金额:
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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:
$ 10.34万 - 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:
$ 10.34万 - 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
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- 批准号:
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