Exploring brain perivascular fibroblasts in health and cerebral amyloid angiopathy

探索大脑血管周围成纤维细胞在健康和脑淀粉样血管病中的作用

基本信息

批准号：
10739076
负责人：
Stephanie Bonney
金额：
$ 13.17万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739076
关键词：
Ablation Acceleration Address Adult Advisory Committees Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Precursor Arteries Astrocytes Biology Blood Vessels Blood flow Brain Calcium Calcium Signaling Cells Cerebral Amyloid Angiopathy Cerebrovascular system Child Clinical Clinical Pathology Communication Complex Coupled Developmental Biology Diameter Disease Disease Progression Endothelial Cells Ensure Etiology Event Extracellular Matrix Proteins Faculty Fibroblasts Functional disorder Future Gene Expression Profile Genes Genetic Transcription Goals Health Hypercapnia Image Impairment Investigation Knowledge Life Mediating Mentorship Methods Microvascular Dysfunction Modeling Mus Mutation Optics Pathology Pathway interactions Peptide Initiation Factors Pericytes Phase Physiology Population Regenerative Medicine Reporter Reporting Research Research Institute Role Running Smooth Muscle Myocytes Structure Techniques Testing Tg2576 Therapeutic Tissues Training Transgenic Organisms Vascular Diseases arteriole awake brain health career constriction experience genetic approach improved in vivo in vivo imaging innovation mouse model neuropathology neurovascular neurovascular coupling skills therapy development tool transcriptomics two photon microscopy vascular factor vasomotion venule wasting

项目摘要

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.

项目摘要保持稳定的脑血管网络对于确保整个生命的整体大脑健康至关重要。血管周细胞（如周细胞和平滑肌细胞）对于维持大脑的完整性至关重要脉管系统。在阿尔茨海默氏病（AD）中注意到周细胞和平滑肌细胞的丧失，并影响血管完整性，最终导致疾病病理学。血管周成纤维细胞（PVF）是另一个细胞沿着脑脉管系统的人群，但是它们的作用在很大程度上尚不清楚。 PVF表达了许多细胞外基质蛋白在小动脉和静脉均具有独特性，而不是毛细血管。我的初步研究表明，PVF在健康中保持血管结构稳定性，尤其是沿动脉的稳定性脑。此外，我发现小动脉在脑淀粉样血管病的小鼠模型中更曲折（CAA），这与PVF的显着降低有关。 CAA是一种小血管疾病，其特征是在AD中通常观察到的血管上的淀粉样蛋白-的积累。小动脉及其立即分离是血液流入大脑的重要主要调节剂。这样，他们经历了广泛的词典和收缩事件可能部分由PVF表达的细胞外基质蛋白支持。目标该建议的是确定PVFS是否调节健康大脑中的动脉结构和动力学。此外，我的目标是了解CAA是否有助于PVF损失，改变动脉结构和通过影响细胞外基质蛋白的表达，最终加剧CAA的动力学。了解大脑脉管系统的这些重要方面，最终可以为开发旨在限制AD病理并改善血管功能的治疗。我将在Andy Shih博士的指导下接受的培训，Andy Shih博士是体内成像和大脑专家健康和疾病中的血管生理学将使我能够实现该提案的目标。我的训练是由我的咨询委员会进一步支持，由Drs组成。史蒂文·格林伯格，理查德·丹曼和蒂莫西·樱桃（Timothy Cherry）将通过提供CAA临床病理学，PVF病理生物学来增强我的培训和单细胞转录组学分别。完成这些研究后，我将获得广泛了解体内成像，复杂的血管生理学和单细胞转录组方法，另外热和CAA病理学中的PVF生物学。这些基本研究和技术是关键的组成部分在本应用程序中描述的我提出的独立阶段中，将推动我未来的目标独立研究小组研究大脑中的小血管疾病。此外，在Shih博士的支持下我的咨询委员会以及发展中心西雅图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，授予技巧，网络和精神训练。通过在我的培训期间继续增强这些关键技能第一阶段将被毒死，以指导自己成功的研究小组。