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 ?-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.
This proposal is designed to train Dr. Margaret Flanagan in formal epidemiologic and translational research approaches to enable her to become an independently funded physician-scientist studying dementia and aging. Trans-active response DNA-binding protein 43 (TDP43) has been previously shown to be associated with increased levels of inflammatory markers and may serve as a modulator of inflammation, yet it remains unclear what is detrimental vs. beneficial in the increasingly prevalent disease entity: Limbic predominant age related TDP43 encephalopathy (LATE). Results from this work will provide insight for development of future therapeutic strategies targeting TDP43 associated neuroinflammation.