Cellular and molecular mechanism of vascular malformations

血管畸形的细胞和分子机制

• 批准号: 503902844
• 负责人: Dr. Michael Orlich
• 金额: --
• 依托单位: Department for Immunology, Genetics and Pathology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/503902844?language=en
• 关键词: Cellular; molecular; mechanism; vascular; malformations

Vascular malformations are alterations in blood vessel morphology and function. They can affect all blood vessel types and range in severity from being asymptomatic to life-threatening. In this application I plan to study Cerebral Cavernous Malformations (CCMs) a disease in which capillary-venous malformations form within the central nervous system. CCM lesions can measure several centimeter in size and affected blood vessels are prone to leak. While CCM is a rare disease, it is devastating for affected individuals that experience severe symptoms including headaches, vision and hearing loss, seizures and paralysis. At present, there is no pharmacological treatment available and the mechanisms that lead to lesion formation remain, in many aspects, poorly understood. My host laboratory has recently shown that the small GTPase CDC42 plays a key role in the pathophysiology of CCM and has developed a CDC42 based animal model to study this disease. Preliminary results suggest the novel concept that endothelial cell migration defects initiate the formation of malformations. Whereas other processes subsequently contribute to lesion expansion and growth. With the experiments outlined in this application I aim to specifically investigate if cell migration defects also contribute to lesion formation in other CCM mouse models and to characterize the cellular and molecular mechanisms that underlay the subsequent lesion expansion. Using single-cell RNA sequencing experiments I will map the transcriptional changes in Cdc42 depleted endothelial cells with the aim to identify potential therapeutic targets as well as useful biomarkers that can help to diagnose the initial steps of lesion formation. I will also study the morphogenetic events and dynamics of lesion formation using intravital imaging. The proposed studies are likely to significantly increase our knowledge about the cellular and molecular mechanisms by which CCM- vascular malformations arise. The gained knowledge, in turn, will be instrumental in designing pharmacological treatment strategies for CCMs.

血管畸形是指血管形态和功能的改变。它们可以影响所有血管类型和严重程度，从无症状到危及生命。在这项应用中，我计划研究脑海绵状畸形(CCM)，这是一种在中枢神经系统内形成毛细血管-静脉畸形的疾病。CCM病变大小可达几厘米，受影响的血管容易渗漏。虽然CCM是一种罕见的疾病，但对于出现头痛、视力和听力丧失、癫痫发作和瘫痪等严重症状的患者来说，它是毁灭性的。目前，还没有可用的药物治疗方法，导致病变形成的机制在许多方面仍然知之甚少。我的宿主实验室最近发现，小GTP酶CDC42在CCM的病理生理学中起着关键作用，并建立了一个基于CDC42的动物模型来研究这种疾病。初步结果提示内皮细胞迁移缺陷启动畸形形成这一新概念。而其他过程随后有助于病变的扩大和生长。通过本申请中概述的实验，我的目标是专门研究细胞迁移缺陷是否也有助于其他CCM小鼠模型中病变的形成，并表征支持后续病变扩展的细胞和分子机制。使用单细胞RNA测序实验，我将绘制耗尽的内皮细胞中的转录变化图，以确定潜在的治疗靶点以及有助于诊断病变形成的初始步骤的有用的生物标记物。我还将利用活体成像研究病变形成的形态发生事件和动力学。拟议的研究可能会显著增加我们对CCM-血管畸形发生的细胞和分子机制的了解。反过来，所获得的知识将有助于设计CCM的药物治疗策略。