This proposal for a five-year mentored research career development project focuses on the study of AIRE protein function in the context of disease-causing mutations. The focused research aim of the proposal is to understand the mechanism by which a novel mutation within the SAND domain of AIRE impairs the protein?s function. The developmental aim of the proposal is further develop the applicant?s capability to understand the functional impact of genetic variation on protein function, ultimately providing the groundwork for research that directly ties genetic variation to clinical disease outcomes. The experiments outlined in the proposal include genetic manipulations of expression vectors, expression of proteins in cell lines, various modes of protein isolation, and immunologic characterization of mutant carrying mice. These experiments will be carried out under the mentorship of Pippa Marrack, M.D., John Kappler, Ph.D., and Mark Anderson, M.D., Ph.D., leaders in the fields of immunology and biochemistry. The candidate is currently an Assistant Professor of Pediatrics at National Jewish Health in the Division of Allergy and Immunology. His primary interest is in monogenetic immune disease. His past work has involved the characterization of novel forms of genetic primary immunodeficiency, and he has collaborated with multiple prominent researchers to characterize novel genetic immune disorders identified in his patients. The outlined proposal builds on the candidate?s previous research and clinical experience in the genetic cause of immune deficiency, dysregulation, and dysfunction by attempting to understand the precise molecular mechanism by which human-based mutations affect the AIRE protein. The development plan dramatically expands the candidate?s capability to understand the relevance of genetic variants to protein structure and function. More specifically, the proposed experiments and didactic work provide the opportunity to understand the function of the AIRE protein, a protein that is essential for normal immune tolerance, and in which he previously identified a novel functional mutation. More generally, the project will position the candidate with a unique set of cross disciplinary skills that will enable him to transition to independence as a highly productive physician scientist in the field of clinical immunology with particular insight into mechanisms of immune tolerance.
Autoimmune diseases affect as many as 50 million Americans of all ethnicities, are a leading cause of death among women, and cost at least 100 billion dollars in the United States yearly, almost twice the economic burden of cancer. This proposal seeks to understand the mechanism by which a poorly understood region of the AIRE protein functions to help ensure that the human immune system does not attack itself. Understanding details of how the AIRE protein works is important for developing genetic screening tools to predict autoimmunity and for developing novel interventions for the prevention and treatment of autoimmunity.