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: 10379950
• 负责人: Donna M Wilcock
• 金额: $ 69.78万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379950
• 关键词: Acute; Address; Aging; Algorithms; Angiogenic Proteins; Animal Model; Antibodies; Astrocytes; Autopsy; Biochemical; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Caliber; Cells; Cerebrovascular system; Chronic; Clinical; Cognition; Data; Dementia; Diet; Diffuse; Distant; Endothelial Cells; Extravasation; Histologic; Histology; Human; Human Characteristics; Hyperhomocysteinemia; Impaired cognition; Individual; Inflammation; Ischemia; Kentucky; Knockout Mice; Length; Longitudinal cohort; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; 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; Western Blotting; White Matter Disease; Wild Type Mouse; angiogenesis; base; cell type; cerebrovascular; cerebrovascular pathology; cohort; digital; digital pathology; exosome; gray matter; human model; human tissue; improved; innovation; interest; intravital imaging; mouse model; 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 弥漫性白色物质病（DWD）是小血管脑血管病变的常见表现， 血管对认知障碍和痴呆（VCID）的关键亚型。但 DWD的机械基础仍然没有完全表征。根据对广泛的 在人类和动物模型的数据中，我们已经鉴定了血管生成介质，特别是胎盘 生长因子（PlGF），因为其与弥漫性白色物质疾病密切相关。 就像视网膜病变中发生的病理性血管生成一样，大脑中的病理性血管生成 导致血脑屏障渗漏，并且与直觉相反，导致组织缺血。我们有令人兴奋的初步 数据表明PlGF和人DWD之间的稳固关系。我们还确定， 与血脑屏障渗漏相关。我们假设PlGF和相关的 血管生成介质，导致病理性血管生成，血管和周围血管渗漏、扭曲 炎症，导致弥漫性白色物质疾病。重要的是，这些病理变化也 代表了一种潜在的靶向机制，以改善衰老中的认知能力。为了验证这些假设， 我们建议在一个广泛表征的人类队列和一个小血管的小鼠模型中进行重点研究， 疾病我们回答“什么，在哪里，为什么”的问题，围绕PlGF。“什么”细胞类型负责 PlGF;“何处”是PlGF被表达;“为什么”是PlGF被上调以及它可以被调节。测试这些 假设，我们建议在一个广泛表征的人类尸检队列和一个小鼠中进行重点研究。 小血管疾病模型： 具体目标1：使用细胞-蛋白质组学方法，确定血浆PLGF和相关血管生成蛋白的贡献。 特异性外泌体及其与脑室周围和深部白色物质病理的相关性。 具体目标2：确定PLGF和相关血管生成蛋白的区域表达， 邻近和远离室周和DWD以及与异常血管生成的相关性。 具体目标3：测试针对以下情况操纵PLGF相关小血管病理的可能性： 高同型半胱氨酸血症（HHcy）引起的小血管疾病。