The role of ATP13A5 ATPase in determining blood-brain pericyte functions

ATP13A5 ATP酶在确定血脑周细胞功能中的作用

• 批准号: 10814088
• 负责人: Zhen Zhao
• 金额: $ 243.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814088
• 关键词: ATP phosphohydrolase; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Astrocytes; Basement membrane; Biological; Biological Assay; Biological Process; Biology; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cell membrane; Cells; Central Nervous System; Central Nervous System Diseases; Charge; Data; Drug Delivery Systems; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Essential Amino Acids; Failure; Fatty Acids; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Models; Glucose; Glucose Transporter; Goals; Heterogeneity; Immune; In Vitro; Ions; Knock-out; Learning; Link; Lipids; Longevity; Maintenance; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Neurotransmitters; Organ; Oxidative Phosphorylation; Pathogenesis; Pericytes; Play; Proteins; Regulation; Reporter; Research; Role; Somatotropin; Structure; System; Tight Junctions; Toxic Environmental Substances; Transgenic Organisms; Vascular System; Visit; Vitamins; Waste Products; biomarker identification; blood-brain barrier function; brain endothelial cell; data mining; drug development; fortification; in vivo; member; metabolomics; molecular pump; neurovascular unit; novel marker; pathogen; programs; protein transport; receptor; seal; tool; transcriptome; transcriptomics; transcytosis; wasting

Abstract The blood-brain barrier (BBB) provides a physical barrier limiting the entrance of circulating pathogens and environmental toxins, immune cells and body’s metabolic waste products into the central nervous system (CNS); it also supplies the brain with critical energy metabolites such as glucose and lactate, essential amino acids, fatty acids and vitamins, and regulatory molecules and growth hormones via selective transport systems. The BBB also helps clear brain’s own metabolic wastes including excess of neurotransmitters and proteinaceous molecules such as Alzheimer’s amyloid-β species (Aβ), providing neurons with a tightly controlled microenvironment. The lessons we learned from the failures of drug development for the neurodegenerative diseases have led us to revisit the BBB in recent years, not only for its contribution to CNS diseases such as Alzheimer’s disease and related dementia (ADRD), but also to circumvent this formidable barrier for drug delivery. The answers may remain in the biological mechanisms that make the BBB fundamentally different from other parts of the vascular system. Therefore, the major goal of the current proposal is to determine the genetic marker(s) that separates the BBB from non-BBB vascular system, and delineate a molecular mechanism that potentially drives the specialization and maintenance of the BBB in animal models. Brain endothelial cells are known to form a more tightly sealed barrier through tight junctions and eliminating transcytosis. They are also in close interactions with astrocytes and perivascular mural cells, resulting in specialized perivascular structures such as the basement membrane, pericyte coverage and astrocytic endfeet. It has been known for nearly a century that vascular cells are heterogeneous even within the brain, and several brain regions are not protected by the BBB, particular the circumventricular organs (CVOs). However, no good marker or genetic tool is available for us to reliably identify and separate the BBB and non-BBB vascular system. Using single cell transcriptomics and data mining, we have identified markers and generated new transgenic tools for separating BBB and non-BBB vascular cells. Therefore, we propose to further determine the heterogeneity of brain endothelial cells and pericytes. As our preliminary data indicate that Atp13a5 is unique to brain pericytes and essential for BBB integrity, we hypothesize that Atp13a5 is acquired by brain pericytes during BBB specialization, and required for pericyte’s role in fortifying the BBB, particularly in aging and Alzheimer’s disease. We plan to determine its biological functions in vitro at molecular and cellular levels, and in vivo using a knockout model. We hope that the new marker and tools will help us to achieve a better understanding of brain vascular biology and heterogeneity in the context of BBB functions, as well as their contributions to CNS disorders, e.g., ADRD.

抽象的 血脑屏障（BBB）提供了一个物理障碍，限制了循环病原体的入口和 环境毒素，免疫细胞和人体的代谢废物产生中枢神经系统（CNS）； 它还为大脑提供关键的能量代谢产物，例如葡萄糖和葡萄糖，必需氨基酸，脂肪 通过选择性传输系统，酸和维生素，调节分子和生长马。 BBB 还有助于清除大脑自己的代谢废物，包括过量的神经递质和蛋白质 分子，例如阿尔茨海默氏症的淀粉样蛋白β（Aβ），为神经元提供紧密控制的神经元 微环境。我们从神经退行性的药物开发失败中学到的教训 近年 阿尔茨海默氏病和相关痴呆症（ADRD），但也要规避这种强大的药物输送障碍。 答案可能保留在生物学机制中，这些机制使BBB根本不同地不同于其他 血管系统的一部分。因此，当前建议的主要目标是确定通用 将BBB与非BBB血管系统分开的标记物，并描绘出一种分子机制 有可能驱动动物模型中BBB的专业化和维护。 已知脑内皮细胞通过紧密连接形成更紧密的屏障并消除 转胞病。它们也与星形胶质细胞和血管周壁细胞密切相互作用，导致 专门的血管周结构，例如地下膜，周细胞覆盖范围和星形胶质细胞终端。 近一个世纪以来，人们已经知道血管细胞即使在大脑中也是异质的，有几个 大脑区域不受BBB的保护，尤其是室内器官（CVO）。但是，没有好处 标记或遗传工具可用于可靠地识别和分离BBB和非BBB血管系统。 使用单细胞转录组学和数据挖掘，我们已经确定了标记并生成了新的转基因 分离BBB和非BBB血管细胞的工具。因此，我们建议进一步确定 脑内皮细胞和周细胞的异质性。因为我们的初步数据表明ATP13A5是独特的 大脑周细胞和BBB完整性必不可少的 BBB专业化，并且需要周围的生物在强化BBB中的作用，尤其是在衰老和阿尔茨海默氏症中 疾病。我们计划在分子和细胞水平的体外确定其生物学功能，并在体内使用 淘汰赛模型。我们希望新的标记和工具将帮助我们更好地了解大脑 在BBB功能的背景下，血管生物学和异质性及其对CNS的贡献 疾病，例如Adrd。