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
• 负责人: Donna M Wilcock
• 金额: $ 10.34万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10597648
• 关键词: Acute; Address; Aging; Algorithms; Angiogenic Proteins; Animal Model; Antibodies; Astrocytes; Autopsy; Biochemical; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular system; Chronic; Circulation; Clinical; Cognition; Data; Dementia; Diameter; Diet; Diffuse; Distant; Endothelial Cells; Extravasation; Hemorrhage; Histologic; Histology; Human; Human Characteristics; Hyperhomocysteinemia; Individual; Infarction; Inflammation; Ischemia; Kentucky; Knockout Mice; Length; Longitudinal cohort; Magnetic Resonance Imaging; Mediating; Mediator; Microglia; Microvascular Dysfunction; Modeling; Molecular; Morphology; Mus; Neurons; Oligodendroglia; PGF gene; Pathologic; Pathologic Neovascularization; Pathology; Plasma; Proteins; Quantitative Reverse Transcriptase PCR; Research Personnel; Resources; Retinal Diseases; Rodent; Role; Sampling; Series; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Universities; Ventricular; Western Blotting; White Matter Disease; Wild Type Mouse; angiogenesis; cell type; cerebrovascular; cerebrovascular pathology; cohort; digital; digital pathology; exosome; gray matter; human model; human tissue; improved; innovation; interest; intravital imaging; mouse model; neuropathology; neurovascular; novel; response; targeted treatment; vascular cognitive impairment and dementia; white matter

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。