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.

摘要 中枢神经系统（CNS），包括大脑，脊髓和视网膜，是最重要的 血管化的器官系统。神经元和神经胶质细胞与血液紧密接触 血管和沟通与血管内皮细胞和周细胞，以控制正常中枢神经系统 发育和生理学。血管功能障碍发生在多种CNS疾病中， 包括大脑发育障碍、视网膜缺陷和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知之甚少。 发育和生理或这些事件在疾病发病过程中如何出错。到 描述控制血管形态发生的新的和潜在的靶向因子， 在发展中的中枢神经系统中，我们查询了开源数据库，以确定在中枢神经系统中具有假定作用的基因。 血管内皮细胞生长、分化和出芽。这些努力导致了 目前的项目集中在Prnd上，Prnd是朊病毒基因家族的一员，表达于 CNS血管内皮。我们提出了大量的数据，支持我们的工作， 糖磷脂酰肌醇（GPI）连接Prnd激活内皮细胞信号转导的假说 调节大脑和视网膜中血管生成和血管渗透性的途径。 此外，我们提出，异常的Prnd表达和功能有助于脑和 视网膜血管病变为了验证我们的假设，我们将（1）利用生物化学 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）分析作用 Prnd在发育和病理性CNS血管生成中的作用;以及（3）鉴定和表征 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CNS中的病理性血管生成。