Genetics of Autontibody Diversification

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DESCRIPTION (provided by applicant): The main objective of this KO1 proposal is for the PI to obtain sufficient training and expertise in the areas of molecular biology and genetics to address important questions in autoimmune disorders. The PI is well trained in immunochemistry and cellular immunology and has developed experimental mouse model systems to study immune responses to autoantigens in systemic lupus erythematosus (SLE). His publication record is outstanding and provides evidence that he has the potential and the quality to develop into a first-rate investigator. He has assembled a team of independent investigators to help him to achieve the stated short-term objective. This period of further training will ensure him to develop into a competitive independent investigator in biomedical research. Dr. Shu Man Fu, Professor and Chief of the Division of Rheumatology and Immunology will serve as the primary mentor. He has an outstanding record in mentoring and significant funding to enable the PI to complete the proposed program. Dr. Michael Brown, Assistant professor in the Division and the co-mentor of the award has successfully mapped the NKC region in the mouse. He has the expertise in many of the approaches used in the proposal. In addition, a group of consultants in the areas of molecular biology and genetics will help the PI. Dr. Gary Litman of the University of South Florida and Dr. Chris Amemiya of the Virginia Mason Medical Center at Seattle will provide intense short period of training in molecular biology and cloning. A well thought-out series of courses at the University and elsewhere will be attended by the PI to ensure the needed basic training in molecular genetics and bioinformatics. The University of Virginia School of Medicine has an interactive environment with outstanding faculty and research facilities. The Division of Rheumatology and Immunology has recruited several independent investigators in both basic and clinical research. The Division is well supported by the Medical School and the Department of Internal Medicine. Thus the environment is outstanding for the further development of the PI and there is strong commitment to him from the Division and the Chair for career development. The proposal addresses the hypothesis that certain genes important in immunoregulation are important for autoantibody diversification to SLE-related autoantigens. Two specific aims are proposed: (1) To define non- MHC genetic loci influencing epitope spreading, and (2). To demonstrate that under an appropriate genetic background, MHC Class II genes dictate epitope spreading. The proposal addresses a significant issue in autoimmunity and will serve well as a training vehicle to obtain the stated goals by the PI.