Analyzing the Endothelial Cell-Expressed Prion Gene Prnd in Vascular Development

血管发育中内皮细胞表达的朊病毒基因 Prnd 的分析

• 批准号: 10388824
• 负责人: Joseph H McCarty
• 金额: $ 40.1万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388824
• 关键词: Adult; Biochemical; Biochemical Genetics; Blood Vessels; Brain; Brain Diseases; Cell Culture System; Cell Surface Proteins; Cell surface; Cells; Central Nervous System Diseases; Chimeric Proteins; Cues; Cytoplasmic Tail; Data; Databases; Defect; Development; Differentiation and Growth; Disease; Endocytosis; Endothelial Cells; Endothelium; Environment; Event; Family member; Fluorescence Microscopy; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Screening; Genetically Engineered Mouse; Growth; Growth Factor; Growth Factor Receptors; Human body; Integral Membrane Protein; Internet; Knowledge; Leukoencephalopathy; Link; Mediating; Morphogenesis; Mus; Neuraxis; Neurodevelopmental Disorder; Neuroglia; Neurons; Normal tissue morphology; Norrie' s disease; Organ; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Pericytes; Perinatal subependymal hemorrhage; Permeability; Pharmacology; Physiology; Play; PrP; Prions; Receptor Protein-Tyrosine Kinases; Recombinants; Resolution; Retina; Retinopathy of Prematurity; Role; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Cord; Structure; Testing; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; Vascular System; age related neurodegeneration; angiogenesis; blood vessel development; body system; cell growth; cellular imaging; experimental study; genetic manipulation; imaging modality; in vivo; member; migration; nervous system development; new therapeutic target; novel; open source; protein protein interaction; retina blood vessel structure; tool; white matter

Abstract The central nervous system (CNS), comprised of the brain, spinal cord and retina, is the most vascularized organ system in the human body. Neurons and glial cells closely contact blood vessels and communicate with vascular endothelial cells and pericytes to control normal CNS development and physiology. Blood vessel dysfunction occurs in multiple CNS diseases, including developmental brain disorders, retinal deficits, and age-related neurodegeneration. We understand surprisingly little about mechanisms that regulate normal CNS vascular development and physiology or how these events go awry during disease pathogenesis. To characterize new and potentially targetable factors that control blood vessel morphogenesis in the developing CNS, we queried open-source databases to identify genes with putative roles in vascular endothelial cell growth, differentiation and sprouting. These efforts have led to the current project focused on Prnd, a member of the prion gene family that is expressed in the CNS vascular endothelium. We present a substantial amount of data that bolster our working hypothesis that glycophosphatidylinositol (GPI)-linked Prnd activates endothelial cell signaling pathways to regulate angiogenesis and blood vessel permeability in the brain and retina. Furthermore, we propose that abnormal Prnd expression and function contributes to brain and retinal blood vessel pathologies. To test our hypotheses, we will (1) utilize biochemical strategies and high-resolution cell imaging methods to analyze Prnd-dependent signaling pathways that promote endothelial cell differentiation, growth and migration; (2) analyze roles for Prnd in developmental and pathological CNS angiogenesis; and (3) identify and characterize cues in the CNS microenvironment that promote Prnd expression and functions in angiogenic endothelial cells. In summary, these experiments will reveal novel functions for Prnd in regulating CNS blood vessel morphogenesis and may identify new targets for therapeutically inhibiting pathological angiogenesis in the CNS.

抽象的 中枢神经系统（CNS）由大脑、脊髓和视网膜组成，是最重要的神经系统。 人体的血管器官系统。神经元和神经胶质细胞与血液密切接触 血管并与血管内皮细胞和周细胞通讯以控制正常的中枢神经系统 发育和生理学。多种中枢神经系统疾病都会出现血管功能障碍， 包括发育性脑部疾病、视网膜缺陷和与年龄相关的神经变性。 令人惊讶的是，我们对调节正常中枢神经系统血管的机制了解甚少 发育和生理学或这些事件在疾病发病机制中如何出错。到 描述控制血管形态发生的新的和潜在的目标因素 对于正在发育的中枢神经系统，我们查询了开源数据库来识别在中枢神经系统中具有推定作用的基因 血管内皮细胞生长、分化和出芽。这些努力导致了 目前的项目重点关注 Prnd，它是朊病毒基因家族的成员，表达于 中枢神经系统血管内皮。我们提供大量数据来支持我们的工作 糖磷脂酰肌醇 (GPI) 连接的 Prnd 激活内皮细胞信号传导的假设 调节大脑和视网膜血管生成和血管通透性的途径。 此外，我们认为异常的 Prnd 表达和功能有助于大脑和 视网膜血管病变。为了检验我们的假设，我们将（1）利用生化 分析 Prnd 依赖性信号传导的策略和高分辨率细胞成像方法 促进内皮细胞分化、生长和迁移的途径； (2)分析角色 用于发育性和病理性中枢神经系统血管生成中的 Prnd； (3) 识别和表征 CNS 微环境中促进 Prnd 表达和血管生成功能的线索 内皮细胞。总之，这些实验将揭示 Prnd 的新功能 调节中枢神经系统血管形态发生并可能确定新的治疗靶点 抑制中枢神经系统的病理性血管生成。