Brain Cholesterol Biosynthesis in Health and Neurological Disease

项目总结 这项应用的目的是建立一个新的框架，以支持对星形胶质细胞作用的研究 神经疾病，包括神经退行性变，以及血管对认知障碍和 痴呆症(VCID)。这项应用的动机是观察到星形胶质细胞功能障碍与脑血管有关 疾病。我们建议通过系统的解剖来研究星形胶质细胞在脑血管畸形中的作用。 CCM3(脑海绵状血管畸形3)在模式生物和原代培养中的功能相关性。损失- CCM3功能缺失突变导致最具侵袭性的家族性脑海绵状血管畸形(CCM)， 以血管病变为特征的常见脑血管病癫痫发作和出血性中风 (称为CCM、海绵状血管瘤或海绵状瘤)位于中枢神经系统。我们正在进行的小鼠研究 模型表明，CCM3在星形胶质细胞中具有独特和特定的功能，除了它在 血管内皮细胞。放射状胶质祖细胞和星形胶质细胞中CCM3缺乏具有细胞固有效应，导致 星形胶质细胞的激活和功能障碍。此外，它还具有细胞非自治效应，并导致广义 小鼠脑血管病理及CCM样病变的形成。拟议的研究利用了动物的优势 我们建立的模型，以及星形胶质细胞的原代培养，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 这两种疾病都与其他神经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，并定义了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是如何导致病理学的。我们的研究具有基本的生物学价值，通过 扩展对CCM3作用的机械性理解，将使我们能够获得可能在治疗上重要的东西 对CCM疾病的洞察。此外，我们的发现有可能在中国建立一种遗传易处理的系统 不仅在CCM，而且在包括VCID在内的其他神经疾病中，研究反应性星形胶质细胞功能障碍 和神经退化。

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.