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.

摘要 血脑屏障(BBB)提供了一种物理屏障，限制循环病原体和 环境毒素、免疫细胞和人体代谢废物进入中枢神经系统(CNS)； 它还为大脑提供关键的能量代谢物，如葡萄糖和乳酸、必需氨基酸、脂肪 酸和维生素，以及调节分子和生长激素通过选择性运输系统。《BBB》 还有助于清除大脑自身的代谢废物，包括过量的神经递质和蛋白质 像阿尔茨海默氏症淀粉样蛋白-β物种(Aβ)这样的分子，为神经元提供了严格控制的 微环境。我们从治疗神经退行性疾病的药物开发失败中吸取的教训 近年来，疾病促使我们重新审视血脑屏障，不仅是因为它对中枢神经系统疾病的贡献，如 阿尔茨海默氏症及相关痴呆症(ADRD)，但也绕过这一可怕的药物输送障碍。 答案可能在于使血脑屏障从根本上不同于其他血脑屏障的生物学机制 血管系统的一部分。因此，目前提案的主要目标是确定基因 标记(S)，分离血脑屏障和非血脑屏障血管系统，并描绘了一个分子机制 潜在地推动动物模型中血脑屏障的专门化和维护。 众所周知，脑内皮细胞通过紧密的连接和清除形成更紧密的屏障 细胞穿透。它们还与星形胶质细胞和血管周围壁细胞密切相互作用，导致 特殊的血管周围结构，如基底膜、周细胞覆盖物和星形细胞终足。 近一个世纪以来，人们已经知道，即使在大脑中，血管细胞也是异质的，而且有几个 大脑区域不受血脑屏障的保护，特别是脑室周围器官(CVO)。然而，这并不是好事 我们可以使用标记或遗传工具来可靠地识别和分离血脑屏障和非血脑屏障血管系统。 利用单细胞转录学和数据挖掘，我们已经确定了标记并产生了新的转基因 分离血脑屏障和非血脑屏障血管细胞的工具。因此，我们建议进一步确定 脑内皮细胞和周细胞的异质性。正如我们的初步数据表明，Atp13a5是 脑周细胞和血脑屏障完整性所必需的，我们假设Atp13a5是由脑周细胞在 血脑屏障特化，周细胞加强血脑屏障的作用，特别是在衰老和阿尔茨海默氏症中 疾病。我们计划在体外从分子和细胞水平确定其生物学功能，并在体内使用 出众的模特。我们希望新的标记和工具将帮助我们更好地了解大脑 血脑屏障功能背景下的血管生物学和异质性及其对中枢神经系统的贡献 疾病，如ADRD。