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.

抽象的 弥漫性白质疾病（DWD）是小血管脑血管病理学和 对认知障碍和痴呆（VCID）的血管贡献的关键亚型。但是， DWD的机械基础仍然没有完全表征。基于广泛的评估 人类和动物模型中的数据，我们已经确定了血管生成介质，特别是placenal 生长因子（PLGF），因为与弥漫性白质疾病密切相关。 就像在视网膜病变中发生的病理血管生成一样，大脑中的病理血管生成 导致血脑屏障泄漏和违反直觉的组织缺血。我们有令人兴奋的初步 数据表明PLGF与人DWD之间的牢固关系。我们还确定PLGF是 与血脑屏障泄漏相关。我们假设PLGF及其相关 血管生成介质，导致病理血管生成，并带有漏水，曲折的血管和周围 炎症，导致弥漫性白质疾病。重要的是，这些病理变化也 代表了改善衰老认知的潜在目标机制。为了检验这些假设， 我们提出了在广泛表征的人类队列中的重点研究和小血管的小鼠模型 疾病。我们回答有关PLGF的“什么，哪里，为什么”问题。 “什么”细胞类型负责 PLGF;表达PLGF的“哪里”； “为什么”上调了“为什么”，并且可以调制它。测试这些 假设，我们在广泛表征的人类尸检队列中提出了重点研究，小鼠 小血管疾病的模型： 特定目标1：使用细胞 - 确定对血浆PLGF的贡献，以及相关的血管生成蛋白 特定的外泌体及其与周期和深白质病理学的关联。 特定目标2：确定PLGF的区域表达以及相关的血管生成蛋白，内部 毗邻并远离周围和DWD以及与异常血管生成的关联。 特定目标3：测试操纵PLGF相关的小血管病理学的潜力 高型结晶血症（HHCY）诱导的小血管疾病。