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 由大脑，脊髓和视网膜组成的中枢神经系统（CNS）是最大的 人体中的血管器官系统。神经元和神经胶质细胞紧密接触血液 血管并与血管内皮细胞和周细胞进行通信以控制正常的中枢神经系统 发展与生理。血管功能障碍发生在多种CNS疾病中， 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。 我们对调节正常CNS血管的机制几乎没有理解 发育和生理学或这些事件在疾病发病机理期间如何出现问题。到 表征控制血管形态发生的新的和潜在的目标因素 开发的CNS，我们询问开源数据库，以识别具有假定角色的基因 血管内皮细胞生长，分化和发芽。这些努力导致了 目前的项目侧重于PRND，PRND是prion基因家族的成员 中枢神经系统血管内皮。我们提供大量的数据来加强我们的工作 假设糖磷脂酰肌醇（GPI）连接的PRND激活内皮细胞信号传导 调节大脑和视网膜中血管生成和血管渗透性的途径。 此外，我们建议异常的PRND表达和功能有助于大脑和 视网膜血管病理。为了检验我们的假设，我们将（1）使用生化 策略和高分辨率细胞成像方法分析PRND依赖性信号传导 促进内皮细胞分化，生长和迁移的途径； （2）分析角色 用于发育和病理中枢神经系统血管生成的PRND； （3）识别和表征 中枢神经系统微环境中促进PRND表达和功能的线索 内皮细胞。总而言之，这些实验将揭示PRND的新功能 调节CNS血管形态发生，并可能确定治疗的新靶 抑制中枢神经系统中的病理血管生成。