PROJECT SUMMARY/ABSTRACT The overall theme of this program project grant is to study the pathophysiology of genetically defined dementia and neurodegeneration to: (i) define therapeutic targets and pathways; (ii) develop small molecule chemical probes to study various modes of toxicity; (iii) develop biomarkers as diagnostics for c9FTD/ALS; and (iv) study the chemical probes in vivo to advance development of pre-clinical candidates. The proposal builds on the significant discoveries made by investigators in this program project and on past collaborations among all of the investigators involved in the P01. The Administrative Core (Core A) is charged with ensuring the success of this research proposal. Core A will have several functions to assure the success of this research proposal. As Core A Leader and Program Project Director, Matthew Disney, Ph.D., is uniquely positioned to leverage available resources to foster a multidisciplinary program project that advances research, generates valuable biological and chemical resources and promotes education on this class of devastating neurological disorders. Core A will have access to administrative assistance with grants administration and all aspects of human subject research. The Aims are: Aim 1. Provide administrative structure and fiscal oversight for the program project grant. Aim 2. Organize regular meetings of the Executive Committee composed of Project and Core Leaders and other key personnel to assist in scientific administration and to facilitate integration and continuing progress on research aims. Aim 3. Establish an external Executive Advisory Committee, conduct annual meetings, and report progress to the NINDS. Aim 4. Report progress to NIH and ensure compliance with the NIH Public Access policy. Aim 5. Enable the program project to transition to the NIH's The Blueprint Neurotherapeutics Network. The overall goal of our collective proposed work is to advance therapeutics and biomarkers to the clinic to treat those afflicted with c9FTD/ALS. Aim 6. Promote education on FTD, ALS and related disorders, and encourage P01 scientists and clinicians to participate in patient and caregiver support groups. Core A will leverage its allocated resources to promote education on FTD, ALS and related disorders at all three institutions, including invited speaker seminar series and various events hosted for the public.