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.
|Fu, Shu Man; Deshmukh, Umesh S; Gaskin, Felicia (2011) Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J Autoimmun 37:104-12|
|Deshmukh, Umesh S; Sim, Davis L; Dai, Chao et al. (2011) HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD. J Autoimmun 37:254-62|
|Jiang, Chao; Deshmukh, Umesh S; Gaskin, Felicia et al. (2010) Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens. J Immunol 184:1085-91|
|Deshmukh, Umesh S; Nandula, Seshagiri Rao; Thimmalapura, Pushpa-Rekha et al. (2009) Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function. J Oral Pathol Med 38:42-7|
|Sharma, Rahul; Deshmukh, Umesh S; Zheng, Lingjie et al. (2009) X-linked Foxp3 (Scurfy) mutation dominantly inhibits submandibular gland development and inflammation respectively through adaptive and innate immune mechanisms. J Immunol 183:3212-8|
|Sim, Davis L; Bagavant, Harini; Scindia, Yogesh M et al. (2009) Genetic complementation results in augmented autoantibody responses to lupus-associated antigens. J Immunol 183:3505-11|
|Zheng, Lingjie; Sharma, Rahul; Kung, John T et al. (2008) Pervasive and stochastic changes in the TCR repertoire of regulatory T-cell-deficient mice. Int Immunol 20:517-23|
|Scindia, Yogesh; Deshmukh, Umesh; Thimmalapura, Pushpa-Rekha et al. (2008) Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus. Arthritis Rheum 58:3884-91|
|Deshmukh, Umesh S; Ohyama, Yukiko; Bagavant, Harini et al. (2008) Inflammatory stimuli accelerate Sjogren's syndrome-like disease in (NZB x NZW)F1 mice. Arthritis Rheum 58:1318-23|
|Sharma, Rahul; Zheng, Lingjie; Deshmukh, Umesh S et al. (2007) A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T cell homeostasis. J Immunol 178:1251-5|
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