Diversity Supplement: Pericyte structural plasticity and cerebrovascular health

多样性补充：周细胞结构可塑性与脑血管健康

• 批准号: 10605744
• 负责人: Andy Y Shih
• 金额: $ 5.56万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605744
• 关键词: Address; Adult; Aging; Alzheimer' s disease related dementia; American; Biomedical Research; Blood Vessels; Blood capillaries; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebral cortex; Cerebral small vessel disease; Cerebrum; Communication; Dementia; Development; Disease Progression; Endothelium; Fibroblasts; Funding; Goals; Histologic; Investigation; Latino; Learning; Maintenance; Mus; Nerve Degeneration; Neurosciences; Optics; Parents; Pathology; Pericytes; Pharmacology; Physiological; Property; Research; Research Support; Resolution; Role; Schools; Smooth Muscle Myocytes; Structure; Students; Talents; Testing; Training; Work; aged; arteriole; career; career preparation; cerebral microvasculature; cerebrovascular health; cerebrovascular pathology; density; design; diversity and inclusion; genetic manipulation; hemodynamics; in vivo two-photon imaging; microvascular pathology; mouse model; normal aging; pre-clinical

PROJECT SUMMARY The purpose of this supplement is to increase diversity in biomedical research by supporting the professional development of Ms. Maria Sosa, a talented Latino-American post-baccalaureate student with a career goal of entering graduate school to study the neuroscience of aging and dementia. The supplement is also designed to enhance the goals of the parent R01 (R01AG062738), entitled “Pericyte structural remodeling in the adult brain and its role in maintenance of capillary function”. Briefly, the parent R01 investigates the structural remodeling of pericytes on the brain microvasculature, which allows the cells to change in size to facilitate coverage of the endothelium. It warrants detailed investigation because it may be a valuable target for mitigating the deleterious effects of pericyte loss, which is now well established as a basis of microvascular pathology in Alzheimer’s disease and related dementias (ADRD). To better understand the mechanism of pericyte remodeling, and the physiological consequence of its alteration, our approach combines high-resolution in vivo two-photon imaging of capillary hemodynamics with optical, pharmacological, and genetic manipulation of pericytes in intact microvascular networks of the cerebral cortex of both normal adult and aged mice. In the lab of Prof. Andy Shih, Maria will receive quality training on preclinical ADRD research and learn approaches to study cerebrovascular pathologies. Her work will enhance the R01 project by: (1) characterizing vascular changes in two mouse models of cerebral amyloid angiopathy (CAA) that we plan to incorporate into our studies, and (2) expanding investigations into perivascular fibroblasts (PVFs), which occupy perivascular niches like mural cells, and have emerging roles in vascular pathology during neurodegeneration. Maria will test the working hypothesis that CAA around capillaries precedes the loss of pericyte number and coverage, which in turn precedes a reduction in capillary density. Further, she will test the working hypothesis that CAA along the walls of cerebral arterioles leads to loss of perivascular fibroblasts, which precedes changes in the vascular structure, such as increased tortuosity, and loss of arteriolar smooth muscle cells. To address these hypotheses, Maria will characterize pericytes, perivascular fibroblasts, and brain vascular properties over the course of disease progression in mouse models of CAA. Throughout these studies, Maria will gain training in histological approaches, brain vascular functionality, and scientific communication in preparation for her career goals. This funding will therefore both increase inclusion and diversity as well as enhance the aims of the parent proposal.

项目摘要 这一补充的目的是增加生物医学研究的多样性，通过支持专业 玛丽亚·索萨女士的发展，一个有才华的拉丁美洲学士学位后的学生，职业目标是 进入研究生院学习衰老和痴呆症的神经科学。该补充还旨在 增强了题为“成人大脑中的周细胞结构重塑”的父研究报告R01（R01AG062738）的目标 及其在维持毛细血管功能中的作用”。简言之，母体R01研究了结构重塑 在大脑微血管上的周细胞，这使得细胞的大小变化，以促进覆盖的 内皮细胞它值得详细调查，因为它可能是一个有价值的目标，以减轻有害的 周细胞损失的影响，这是现在很好地建立了微血管病理学的基础，在阿尔茨海默氏症 疾病及相关痴呆（ADRD）。为了更好地理解周细胞重塑的机制， 生理后果的改变，我们的方法结合高分辨率在体内双光子成像 毛细血管血流动力学的光学，药理学，和遗传操作的周细胞在完整的 正常成年和老年小鼠大脑皮层的微血管网络。在施安迪教授的实验室里， 玛丽亚将接受临床前ADRD研究的质量培训，并学习研究脑血管的方法 病理学她的工作将通过以下方式增强R01项目：（1）描述两种小鼠模型中的血管变化 脑淀粉样血管病（CAA），我们计划纳入我们的研究，（2）扩大 血管周围成纤维细胞（PVF）的研究，占据血管周围壁龛像壁细胞， 在神经变性过程中血管病理学中的新作用。玛丽亚将测试CAA的工作假设， 在毛细血管周围，周细胞数量和覆盖率的损失，这反过来又导致减少， 毛细管密度此外，她将测试CAA沿着大脑小动脉壁的工作假设， 导致血管周围成纤维细胞的损失，这先于血管结构的变化，如增加的 弯曲和小动脉平滑肌细胞的损失。为了解决这些假设，玛丽亚将描述 周细胞、血管周围成纤维细胞和脑血管特性在疾病进展过程中的作用 CAA小鼠模型。通过这些研究，玛丽亚将获得组织学方法，脑 血管功能和科学交流，为她的职业目标做准备。这笔资金将 两者都增加了包容性和多样性，并加强了母提案的目标。