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）提供了限制循环病原体进入的物理屏障， 环境毒素、免疫细胞和身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 通过选择性运输系统输送酸和维生素、调节分子和生长激素。血脑屏障 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 阿尔茨海默病β淀粉样蛋白 (Aβ) 等分子，为神经元提供严格控制的 微环境。我们从神经退行性疾病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，这不仅是因为它对中枢神经系统疾病的贡献，例如 阿尔茨海默氏病和相关痴呆症（ADRD），也是为了规避这一药物输送的巨大障碍。 答案可能仍然存在于使 BBB 与其他生物根本不同的生物机制中。 血管系统的一部分。因此，当前提案的主要目标是确定遗传 将 BBB 与非 BBB 血管系统分开的标记物，并描绘了一种分子机制 潜在地推动动物模型中 BBB 的专业化和维护。 众所周知，脑内皮细胞通过紧密连接形成更紧密密封的屏障并消除 转胞吞作用。它们还与星形胶质细胞和血管周围壁细胞密切相互作用，从而导致 特殊的血管周围结构，如基底膜、周细胞覆盖和星形细胞末足。 近一个世纪以来，人们就知道即使在大脑内，血管细胞也是异质的，并且有几个 大脑区域不受血脑屏障的保护，特别是室周器官（CVO）。然而，没有什么好的 标记或遗传工具可让我们可靠地识别和分离 BBB 和非 BBB 血管系统。 利用单细胞转录组学和数据挖掘，我们已经鉴定了标记并产生了新的转基因 用于分离 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。我们的初步数据表明 Atp13a5 是独一无二的 脑周细胞对于 BBB 完整性至关重要，我们假设 Atp13a5 是由脑周细胞在 BBB 专门化，是周细胞在强化 BBB 中发挥作用所必需的，特别是在衰老和阿尔茨海默病中 疾病。我们计划在分子和细胞水平上确定其体外生物学功能，并利用 淘汰赛模型。我们希望新的标记和工具能够帮助我们更好地了解大脑 BBB 功能背景下的血管生物学和异质性及其对 CNS 的贡献 疾病，例如 ADRD。