Mechanisms of hypoxia induced exacerbation of cerebral cavernous malformations

缺氧导致脑海绵状血管瘤加重的机制

• 批准号: 10367164
• 负责人: Miguel Alejandro Lopez-Ramirez
• 金额: $ 48.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367164
• 关键词: Adult; Affect; Altitude; Animal Model; Apoptosis; Astrocytes; Biological; Biological Factors; Blood; Blood Vessels; Brain; Brain hemorrhage; CCM1 gene; Cardiovascular Diseases; Child; Chronic; Chronic lung disease; Clinical; Coculture Techniques; Combined Modality Therapy; Data; Development; Disease; Endothelial Cells; Endothelium; Environment; Environmental Risk Factor; Extravasation; Gene Expression; Genes; Genetic; Genetic Polymorphism; Gliosis; Goals; Hemorrhage; Heterogeneity; Human; Hypoxia; In Vitro; Individual; Inflammatory; Intervention; Intracranial Hemorrhages; Knock-out; Lead; Lesion; Literature; Messenger RNA; Methods; Modeling; Mus; Neuraxis; Neurologic Deficit; Neurons; Obstructive Sleep Apnea; Oxygen; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Predisposition; Preventive measure; Proteins; Research; Ribosomes; Risk; Risk Factors; Role; Seizures; Severity of illness; Signal Transduction; Site; Stroke; TNFSF5 gene; Testing; Tissues; Translating; Vascular Diseases; Vascular Endothelial Growth Factors; base; brain endothelial cell; brain size; cerebral cavernous malformations; gut microbiome; hypoxia inducible factor 1; in vitro Model; lifetime risk; loss of function mutation; modifiable risk; mouse model; neurovascular; normoxia; novel therapeutic intervention; prevent; profiles in patients; programs; response; stroke risk; vascular abnormality

Cerebral Cavernous Malformations (CCMs) are common neurovascular lesions made of endothelium clusters filled with blood surrounded by gliosis. CCMs affect ~1/200 children and adults, causing a lifetime risk of hemorrhagic strokes and neurologic deficits for which there is no current effective pharmacologic therapy. Loss of function mutations in three CCM genes propels brain vascular changes. However, the propensity of CCM lesions to form in the central nervous system (CNS) parenchyma relative to other tissues has not been fully explained, and the heterogeneity in disease severity suggests that environmental or biological factors (e.g. other genes, neural cells) act as disease modifiers. We and others have demonstrated that increased vascular endothelial growth factor (VEGF) signaling and associated vascular leakage are significant contributors to CCM disease. Our preliminary data show that hypoxic conditions contribute to an aggressive onset and progression of CCM disease. We observed that hypoxia acts as an accelerant of CCM disease by exacerbating the number and size of brain vascular lesions in CCM animal models. We also observed that mouse and human CCM tissue results in increased hypoxia-inducible factor 1 alpha (HIF-1a) activity, and that proliferative astrocytes influence CCM pathogenesis. The proposed study will test the hypothesis that hypoxia exacerbates CCMs through hypoxic programs from astrocytes and endothelium, leading to abnormal vascular development and stroke due to intracranial hemorrhage. Moreover, we hypothesize that intermittent hypoxia (that occurs with patients with obstructive sleep apnea) will further exacerbate CCMs. Specific Aim 1 will test the hypothesis that hypoxia exacerbates CCM formation by elevating hypoxia-driven genes in astrocytes in murine CCM. We will investigate the effect of hypoxia on astrocyte gene expression (e.g., hypoxic program, VEGF) by profiling translated mRNAs obtained from the purification of the EGFP-tagged ribosome in astrocytes in the presence or absence of CCM lesions. Co-culture in vitro models will be used to define the interaction between CCM endothelium and astrocytes that propels vascular dysfunction. Specific Aim 2 will test the hypothesis that hypoxia exacerbates CCM formation by HIF-1a protein stabilization in the brain endothelium in murine CCM. We will investigate the role of endothelial HIF-1a on changes in the endothelial barrier function, gene expression, VEGF signaling using CCM mouse models. Specific Aim 3 will test the hypothesis that intermittent hypoxia exacerbates murine CCM. We will investigate the role of intermittent hypoxia-driven CCM lesion burden, using mouse models of CCM under intermittent hypoxia that partially recapitulates nocturnal oxygen profile in patients with obstructive sleep apnea (OSA). The proposed research may lead to a new therapeutic approach (e.g., combination therapies for activated astrocytes and CCM endothelium) and preventive measures by defining how environmental (e.g., high altitude) or pathological factors (e.g., OSA, chronic lung disease) that alter oxygen levels may act as risk factors for patients affected with CCMs.

脑海绵状血管瘤 (CCM) 是由内皮簇构成的常见神经血管病变 充满血液，周围有神经胶质增生。 CCM 影响约 1/200 的儿童和成人，导致终生风险 目前尚无有效药物治疗的出血性中风和神经功能缺损。损失 三个 CCM 基因的功能突变推动脑血管变化。然而，CCM 的倾向 相对于其他组织，中枢神经系统 (CNS) 实质中形成的病变尚未完全了解 解释，并且疾病严重程度的异质性表明环境或生物因素（例如其他 基因、神经细胞）充当疾病调节剂。我们和其他人已经证明，增加血管 内皮生长因子 (VEGF) 信号传导和相关血管渗漏是 CCM 的重要促成因素 疾病。我们的初步数据表明，缺氧条件会导致侵袭性发作和进展 CCM 疾病。我们观察到，缺氧会加剧 CCM 疾病的数量，从而成为 CCM 疾病的加速剂。 CCM 动物模型中脑血管病变的大小和大小。我们还观察到小鼠和人类 CCM 组织 导致缺氧诱导因子 1 α (HIF-1a) 活性增加，并且增殖星形胶质细胞影响 CCM 发病机制。拟议的研究将检验缺氧通过以下方式加剧 CCM 的假设： 星形胶质细胞和内皮细胞的缺氧程序，导致血管发育异常和中风 以致颅内出血。此外，我们假设间歇性缺氧（发生于患有以下疾病的患者） 阻塞性睡眠呼吸暂停）将进一步加剧 CCM。具体目标 1 将检验缺氧这一假设 通过提高小鼠 CCM 星形胶质细胞中缺氧驱动的基因，加剧 CCM 形成。我们将 通过分析研究缺氧对星形胶质细胞基因表达（例如缺氧程序、VEGF）的影响 在存在或存在的情况下，从星形胶质细胞中纯化 EGFP 标记的核糖体获得翻译的 mRNA 无 CCM 病变。体外共培养模型将用于定义 CCM 之间的相互作用 内皮细胞和星形胶质细胞促进血管功能障碍。具体目标 2 将检验以下假设： 缺氧通过稳定小鼠脑内皮细胞中的 HIF-1a 蛋白加剧 CCM 形成 CCM。我们将研究内皮 HIF-1a 对内皮屏障功能、基因变化的作用 使用 CCM 小鼠模型进行表达、VEGF 信号传导。具体目标 3 将检验以下假设： 间歇性缺氧会加剧小鼠 CCM。我们将研究间歇性缺氧驱动的 CCM 的作用 损伤负担，使用间歇性缺氧下的 CCM 小鼠模型，部分重现夜间 阻塞性睡眠呼吸暂停 (OSA) 患者的氧气状况。拟议的研究可能会带来新的 治疗方法（例如，针对活化星形胶质细胞和 CCM 内皮细胞的联合疗法）以及 通过定义环境（例如高海拔）或病理因素（例如 OSA、 改变氧水平的慢性肺病）可能是受 CCM 影响的患者的危险因素。