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

项目总结 这份NIH职业发展奖提案描述了一项为期五年的职业发展和培训计划 玛格丽特·弗拉纳根博士，实验室神经病理科内科科学家 明尼苏达大学的医学和病理学专业。她的长期目标是成为一名独立的， 内科科学家领袖，将在痴呆症研究领域做出重大贡献。她的事业 发展培训计划包括以下内容：有保障的研究时间，有重点的正规研究生课程 旨在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，具有 由经验丰富的资深科学家组成的多学科团队，以及专注于调查角色的研究经验 以边缘为主的年龄相关性TDP43脑病(晚期)的神经炎症。这项培训计划 最终将由一名准备好的调查员成功申请独立研究资金 在变革性变革中发挥积极领导作用，从而改善卫生保健结果 与反式反应结合蛋白43(TDP43)相关炎症相关的痴呆，包括 阿尔茨海默病(AD)、老年性海马硬化和额颞叶痴呆。 TDP43是一种高度保守的核蛋白，在多种细胞功能中发挥作用，包括 RNA处理。最近，有研究表明，与年龄相关的痴呆症风险增加归因于 多种共存的脑部病变的积累，每一种病变都极大地增加了痴呆症的风险。 由于TDP43或α-突触核蛋白还没有可靠的生物标志物，目前还不可能准确地 检测体内所有共存的损伤，将这些综合评估限制在对 大脑。 这项拟议研究的目的是阐明神经炎症在晚期临床疾病中的作用。 进步。弗拉纳根博士将研究与TDP43相关的炎症标志物 兴趣、共存的神经病理损害、晚期遗传风险变异和认知表现数据 来自梅奥诊所的特征良好的样本。这项工作将介绍与TDP43相关的作用 神经炎症在晚年认知障碍和痴呆的发展中，并最终使 未来预防和治疗干预措施的发展。这项研究将提供一些 最近关于神经炎的第一条信息。 总之，在明确定义的培训、研究和培训的背景下，制定全面的职业发展计划 导师结构将使弗拉纳根博士成为一名成功的、独立的内科科学家。

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.