Investigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy

项目摘要 这个NIH职业发展奖提案描述了一个五年职业发展和培训计划， 博士Margaret Flanagan，实验室神经病理学部门的医生兼科学家 明尼苏达大学医学与病理学系。她的长期目标是成为一个独立的， 他是一位医学科学家领袖，将在痴呆症研究领域做出重大贡献。她的职业生涯 发展培训计划包括以下内容：保护研究时间，重点正规研究生课程 有针对性地提高她在流行病学方面的知识和技能，这是一个结构化的指导计划， 由经验丰富的资深科学家组成的多学科团队，以及调查作用的重点研究经验 边缘系统占主导地位的年龄相关性TDP 43脑病（LATE）的神经炎症。本培训计划 将导致一个成功的申请独立的研究资金的研究者谁是准备 在变革中发挥积极的领导作用，从而改善医疗保健成果， 与反式反应结合蛋白-43（TDP 43）相关的炎症相关的痴呆，包括 阿尔茨海默病（Alzheimer Disease，AD）、海马硬化和额颞叶痴呆。 TDP 43是一种高度保守的核核糖蛋白，在多种细胞功能中发挥作用，包括 RNA加工最近，研究表明，与年龄相关的痴呆风险增加归因于 多个共存的脑损伤的累积，其中每一个都显着增加痴呆症的风险。 由于TDP 43或α-突触核蛋白没有可靠的生物标志物，因此目前不可能准确地 检测体内所有共存病变，将这些综合评估限制在尸检研究中。 个脑袋 这项研究的目的是阐明神经炎症在晚期临床疾病中的作用 进展Flanagan博士将研究与TDP 43相关的炎症标志物， 兴趣、共存神经病理学病变、晚期遗传风险变异和认知表现数据， 来自马约诊所的充分表征的样品。这项工作将告知TDP 43相关的作用 神经炎症在认知障碍和老年痴呆症的发展中的作用， 未来预防和治疗干预措施的发展。这项研究将提供一些 关于晚期神经炎症的第一个信息。 总而言之，在明确的培训、研究和培训框架内制定全面的职业发展计划， 导师制结构将使弗拉纳根博士成为一个成功的，独立的医生科学家。

PROJECT SUMMARY This NIH Career Development Award proposal describes a five-year career development and training plan for Dr. Margaret Flanagan, a physician-scientist in the Division of Neuropathology in the Department of Laboratory Medicine and Pathology at the University of Minnesota. Her long-term goal is to become an independent, physician-scientist leader who will make significant contributions in the field of dementia research. Her career development training plan includes the following: protected research time, focused formal graduate coursework targeted to advance her knowledge and skills in Epidemiology, a structured mentoring program with a multidisciplinary team of experienced senior scientists, and focused research experience investigating the role of neuroinflammation in Limbic predominant age-related TDP43 encephalopathy (LATE). This training plan will culminate in a successful application for independent research funding by an investigator who is prepared to take an active leadership role in transformative change leading to improved health care outcomes in dementias associated with transactive response binding protein-43 (TDP43) associated inflammation, including Alzheimer Disease (AD), hippocampal sclerosis of aging and frontotemporal dementia. TDP43 is a highly conserved nuclear riboprotein that plays a role in a variety of cellular functions including RNA processing. More recently, it has been shown that age-related increases in dementia risk are attributed to the accumulation of multiple co-existing brain lesions, each of which contributes significantly to dementia risk. Because there are no reliable biomarkers for TDP43 or α-synuclein, it is currently impossible to accurately detect all co-existing lesions in vivo, limiting these comprehensive assessments to postmortem studies of the brain. The objective of this proposed research is to clarify the role of neuroinflammation in LATE clinical disease progression. Dr. Flanagan will investigate TDP43 associated inflammatory markers relevant to pathways of interest, co-existing neuropathologic lesions, LATE genetic risk variants and cognitive performance data in well-characterized samples from Mayo Clinic. This work will inform on the role of TDP43-associated neuroinflammation in the development of cognitive impairment and dementia in late life and ultimately, enable the development of future preventative and therapeutic interventions. This research will provide some of the first information about neuroinflammation in LATE. In summary, a comprehensive career development plan in the context of a well-defined training, research and mentorship structure will allow Dr. Flanagan to become a successful, independent physician-scientist.