PROJECT SUMMARY/ABSTRACT Dystonia is a disabling neurologic disorder, affecting more than 3 million people worldwide. It is characterized by involuntary, painful muscle contractions that cause twisting movements leading to abnormal postures. Though dystonia can affect any region of the body, cervical dystonia (CD) is the most common presentation. CD has great etiologic heterogeneity, and the vast majority of cases are idiopathic. Identification of potential pathogenic mechanisms is critical to the development of better diagnostic tools and treatment strategies. With the support of this K23 award, Laura Scorr, MD, MSc, will define the role of immune mechanisms in CD. She will leverage a local biobank in combination with brain specimens from the NIH NeuroBioBank, a unique and powerful national resource for investigators utilizing human post-mortem brain tissue and related biospecimens for their research to understand conditions of the nervous system. The proposed studies will analyze immune cell frequencies (Aim 1), delineate indices of altered immune cell function and activation (Aim 2), and compare histopathologic markers of immune activation in key brain regions implicated in dystonia pathogenesis (Aim 3) in CD as compared to healthy controls. This research strategy will facilitate a 5-year career development and training plan enabling Dr. Scorr to build on her background in statistical computing and clinical epidemiology and to gain critical mentored research training. To achieve independence as a clinical investigator with a unique niche in the immunology of dystonia, Dr. Scorr requires further training in: 1) neuroimmunology; 2) quantitative neuroanatomical methods for detection of neuroimmune activity; and 3) bioinformatics and data science for the identification of pathogenic pathways. To achieve these training aims, Dr. Scorr has assembled a multidisciplinary mentorship team that includes lead mentor Dr. Hyder A. Jinnah, an expert in the biology of dystonia, co-mentor Dr. William Tyor, an internationally recognized expert in translational neuroimmunology research, co-mentor Dr. Jeremy Boss, a world-renowned immunologist, and co-mentor Dr. Yan Sun, an expert in the analytic methods utilized for the discovery of potential pathogenic pathways. Emory University provides an exceptional intellectual and collaborative environment for this research. By leveraging existing biobanks at Emory and through the NIH NeuroBioBank, in combination with the support from her outstanding mentorship team, Dr. Scorr will be well positioned to carry out the proposed study aims and training plan. In doing so, she will develop the expertise and preliminary data to be competitive for NIH R01 and other funding using immunophenotyping, transcriptomic, and neuroanatomical approaches to better understand dystonia biology, inform clinical care, and the direct development of novel therapeutics.