Brain Cholesterol Biosynthesis in Health and Neurological Disease

健康和神经系统疾病中的脑胆固醇生物合成

• 批准号: 10574830
• 负责人: Angeliki Louvi
• 金额: $ 46.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574830
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Animal Model; Astrocytes; Attention; Attenuated; Biochemical; Biological; Biology; Blood Vessels; Brain; Brain hemorrhage; Cavernous Hemangioma; Cell model; Cells; Cerebrovascular Disorders; Childhood; Cholesterol; Cholesterol Homeostasis; Cultured Cells; Dementia; Development; Disease; Disease model; Enzymes; Feedback; Focal Neurologic Deficits; Functional disorder; Genes; Genetic; Goals; Health; Hemorrhage; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Impaired cognition; In Vitro; Inherited; Intervention; Investigation; Lesion; Life; Link; Mediating; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Online Mendelian Inheritance In Man; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Physiology; Process; Production; Protein-Serine-Threonine Kinases; Proteins; Radial; Research; Role; Seizures; Signal Transduction; Spinal Cord; Symptoms; System; Therapeutic; Transcript; Transcription Coactivator; Up-Regulation; Vascular Endothelial Cell; Work; base; cell type; cerebral cavernous malformations; cerebrovascular; cholesterol biosynthesis; in vivo; insight; lipid metabolism; loss of function mutation; malformation; mevalonate; mouse model; neocortical; nervous system disorder; novel; prevent; progenitor; therapeutic target; therapeutically effective; transcriptome sequencing; transcriptomics; vascular cognitive impairment and dementia

PROJECT SUMMARY The objective of this application is to establish a novel framework to support investigations into the role of astrocytes in neurological disease, including neurodegeneration, as well as vascular contributions to cognitive impairment and dementia (VCID). The application is motivated by observations linking astrocyte dysfunction to cerebrovascular disease. We propose to investigate the role of astrocytes in cerebrovascular malformations by systematically dissecting the functional relevance of CCM3 (Cerebral cavernous malformation 3) in model organisms and primary cultures. Loss- of-function mutations in CCM3 cause the most aggressive form of familial Cerebral Cavernous Malformations (CCM), a common cerebrovascular disease of seizures and hemorrhagic stroke characterized by the presence of vascular lesions (known as CCMs, cavernous angiomas, or cavernomas) in the central nervous system. Our ongoing research in mouse models suggested that CCM3 has unique and specific functions in astrocytes, in addition to its established role in vascular endothelial cells. CCM3 deficiency in radial glia progenitors and astrocytes has cell-intrinsic effects, leading to astrocyte activation and dysfunction. In addition, it has cell non-autonomous effects, and results in generalized cerebral vascular pathology and formation of CCM-like lesions in mice. The proposed studies take advantage of animal models we generated, as well as primary cultures of astrocytes, aiming to investigate the consequences of CCM3 deficiency in astrocytes at the structural and molecular level, with attention to astrocyte reactivity and cholesterol production, both of which have been linked to other neurological and neurodegenerative disorders. By elucidating cell intrinsic functions of CCM3 in astrocytes and defining the molecular cascade that mediates its actions, we aim to understand how astrocyte dysfunction contributes to pathology. Our studies carry basic biological value and, by extending mechanistic understanding of CCM3 action, will allow us to gain what may be therapeutically important insights into CCM disease. Moreover, our findings have the potential to establish a genetically tractable system in which to investigate reactive astrocyte dysfunction not only in CCM, but in other neurological diseases, including VCID and neurodegeneration.

项目概要 该应用程序的目的是建立一个新的框架来支持星形胶质细胞作用的研究 神经系统疾病，包括神经变性，以及血管对认知障碍的影响 痴呆症（VCID）。该应用的动机是观察星形胶质细胞功能障碍与脑血管疾病之间的联系 疾病。我们建议通过系统地解剖星形胶质细胞在脑血管畸形中的作用 CCM3（脑海绵状血管瘤 3）在模型生物和原代培养物中的功能相关性。损失- CCM3 的功能丧失突变会导致最具侵袭性的家族性脑海绵状血管畸形 (CCM)，这是一种 常见的脑血管疾病，包括癫痫发作和出血性中风，其特征是存在血管病变 （称为 CCM、海绵状血管瘤或海绵体瘤）发生在中枢神经系统中。我们正在进行的小鼠研究 模型表明，CCM3 除了在星形胶质细胞中的既定作用外，在星形胶质细胞中还具有独特且特定的功能。 血管内皮细胞。放射状胶质祖细胞和星形胶质细胞中的 CCM3 缺乏具有细胞内在效应，导致 星形胶质细胞的激活和功能障碍。此外，它还具有细胞非自主效应，并导致广义 小鼠脑血管病理学和 CCM 样病变的形成。拟议的研究利用了动物 我们生成的模型以及星形胶质细胞的原代培养物，旨在研究 CCM3 的后果 星形胶质细胞在结构和分子水平上的缺陷，注意星形胶质细胞的反应性和胆固醇 产生，这两者都与其他神经系统和神经退行性疾病有关。通过阐明细胞 CCM3 在星形胶质细胞中的内在功能并定义介导其作用的分子级联，我们的目标是 了解星形胶质细胞功能障碍如何导致病理学。我们的研究具有基本的生物学价值，并且通过 扩展对 CCM3 作用机制的理解，将使我们获得可能具有治疗重要性的知识 对 CCM 疾病的见解。此外，我们的研究结果有可能在以下领域建立一个遗传易处理的系统： 不仅可以研究 CCM 中的反应性星形胶质细胞功能障碍，还可以研究其他神经系统疾病（包括 VCID）中的反应性星形胶质细胞功能障碍 和神经退行性变。