Exploring brain perivascular fibroblasts in health and cerebral amyloid angiopathy

项目总结 维持稳定的脑血管网络对于确保终生大脑健康至关重要。 血管周围细胞，如周细胞和平滑肌细胞，对维持大脑的完整性至关重要。 脉管系统。周细胞和平滑肌细胞的丢失在阿尔茨海默病(AD)中被注意到，并影响 血管完整性，最终导致疾病病理。血管周围成纤维细胞(PVF)是另一种细胞 然而，它们的作用在很大程度上是未知的。PVF表示了无数 细胞外基质蛋白，仅存在于小动脉和小静脉上，但不存在于毛细血管中。我的初选 研究表明，在健康人中，PVF保持了血管结构的稳定性，特别是沿小动脉 大脑。此外，我发现在脑淀粉样血管病(CAA)的小鼠模型中，小动脉更加曲折， 这与PVF的显著减少有关。CAA是一种小血管疾病，其特征是 淀粉样蛋白-在AD常见的血管上积聚。小动脉和它们的直接分支是 重要的血液流入大脑的主要调节器。在这样做的过程中，它们经历了广泛的扩张和 收缩事件，可能部分由PVF表达的细胞外基质蛋白支持。目标是 这项建议的目的是确定PVF是否调节健康大脑中的小动脉结构和动力学。 此外，我的目标是了解CAA是否导致PVF丢失、改变小动脉结构和 通过影响细胞外基质蛋白的表达来影响动力学，最终加剧CAA。 了解脑血管系统的这些重要方面最终可能为 开发旨在限制AD病理和改善血管功能的治疗方法。 我将在在体成像和大脑方面的专家施安迪博士的指导下接受培训 血管生理学在健康和疾病方面，将使我能够实现这一建议的目标。我的训练是 进一步得到我的顾问委员会的支持，该委员会由Steven Greenberg博士、Richard Daneman博士和 Timothy Cherry将通过提供CAA临床病理学、PVF病理生物学方面的指导来加强我的培训 和单细胞转录组。完成这些研究后，我将获得广泛的收获 了解活体成像、复杂血管生理学和单细胞转录方法 到健康中的PVF生物学和CAA病理学。这些基础研究和技术是至关重要的组成部分 我在此应用程序中描述的提议的独立阶段，并将推动我未来的目标 研究大脑小血管疾病的独立研究小组。此外，在施博士的支持下， 我的顾问委员会和西雅图发展中心儿童研究所的教职员工 生物学和再生医学，我将扩大我在科学交流方面的经验， 资质、人脉和导师。通过在我的培训期间继续加强这些关键技能 第一阶段将很好地指导我自己的一个成功的研究小组。

PROJECT SUMMARY Maintaining a stable brain vascular network is crucial for ensuring overall brain health throughout life. Perivascular cells, like pericytes and smooth muscle cells, are crucial to maintain the integrity of the brain vasculature. Loss of pericytes and smooth muscle cells are noted in Alzheimer’s Disease (AD) and affects vascular integrity, ultimately contributing to disease pathology. Perivascular fibroblasts (PVFs) are another cell population along the brain vasculature, however their role is largely unknown. PVFs express numerous extracellular matrix proteins that are uniquely found on arterioles and venules but not capillaries. My preliminary investigations indicate that PVFs maintain vessel structural stability, particularly along arterioles, in the healthy brain. Further, I find that arterioles are more tortuous in a mouse model of cerebral amyloid angiopathy (CAA), and this is associated with a significant reduction in PVFs. CAA is a small vessel disease characterized by the accumulation of amyloid- on vessels commonly observed in AD. Arterioles and their immediate off-shoots are important major regulators of blood flow into the brain. In doing so, they undergo extensive dilation and constriction events which is likely supported in part by extracellular matrix proteins expressed by PVFs. The goal of this proposal is to determine if PVFs regulate arteriole structure and dynamics in the healthy brain. Further, my goal is to understand if CAA contributes to PVF loss, altering arteriole structure and dynamics by affecting the expression of extracellular matrix proteins, ultimately exacerbating CAA. Understanding these important aspects of the brain vasculature could ultimately provide a potential for developing therapeutics aimed at limiting AD pathology and improve vascular function. The training I will receive under the guidance of Dr. Andy Shih, who is an expert in in vivo imaging and brain vascular physiology in health and disease, will enable me to achieve the goals of this proposal. My training is further supported by my advisory committee, consisting of Drs. Steven Greenberg, Richard Daneman, and Timothy Cherry who will enhance my training by providing guidance in CAA clinical pathology, PVF pathobiology and single-cell transcriptomics, respectively. Upon completion of these studies, I will have gained extensive knowledge of in vivo imaging, complex vascular physiology and single-cell transcriptomic approaches, in addition to PVF biology in heath and CAA pathology. These foundational studies and techniques are crucial components of my proposed independent phase described in this application and will propel my future goals of running an independent research group studying small vessel diseases in the brain. Further, with the support of Dr. Shih, my advisory committee, and the faculty at Seattle Children’s Research Institute in the Center of Developmental Biology and Regenerative Medicine, I will have expanded my experience in scientific communication, grantsmanship, networking, and mentorship. By continuing to strengthen these crucial skills during my training phase I will be well poised to guide a successful research group of my own.