The PI seeks to develop a career as a physician-scientist focused on the problem of restoring and maintaining immune tolerance in individuals with Type 1 diabetes (T1D) by extending his scientific training in the exceptional environment at Vanderbilt University Medical Center. The failure of immune tolerance is an important underpinning of all human autoimmune diseases. When tolerance fails, autoimmune processes damage vital organs in tens of millions of patients worldwide. The applicant will focus on this scientific challenge through fundamental investigation of the most common pediatric autoimmune disorder-T1D, which afflicts more than 2 million Americans. To prevent and reverse this disease, it is necessary to restore immune tolerance to islet antigens. Most present efforts focus on either limiting the activation of islet-destructive T lymphocytes or enhancing the capacity of certain islet-protective T cells for immune regulation. Significantly, B lymphocytes also play a key role in the disease process both through the production of autoantibodies, which predict disease risk, and by the action of B lymphocytes as requisite antigen presenting cells. Targeting these cells with the B cell depleting agent rituximab has been at least as effective as T cell targeted agents, such as anti-CD3, in slowing the progression of new-onset diabetes. Moreover, studies in a relevant murine model of human T1D suggest a role of regulatory B cells in this salutary effect. These regulatory functions of B cells have also been observed in other models of autoimmune disease, and the applicant has previously characterized their role in transplantation tolerance. Building on these seminal data, we hypothesize that B lymphocytes play a regulatory role in the establishment and maintenance of peripheral immune tolerance and that this capacity is disrupted in T1D. This proposal investigates testable hypotheses which will focus on defining the regulatory functions of B lymphocytes that contribute to islet tolerance by determining: the role of classical B cell subsets, antigen specificity and developmental signals in regulatory B cell function (Aim 1), and their cellular targets and the mechanisms through which their regulatory function is controlled (Aim 2). The environment at Vanderbilt University is poised to address this fundamental biologic question given the local expertise in B lymphocyte immunobiology, the exceptional training atmosphere created by the Vanderbilt Diabetes Center, and the dedication to physician-scientist development exemplified by the Departments of Pediatrics and Microbiology and Immunology. Investigation of these novel hypotheses under the guidance of an exceptional mentoring committee and supported by these outstanding resources will allow the PI to realize a significant opportunity for new discovery in this clinically relevant field of inquiry-the fundamental problem of lost tolerance in T1D.

Public Health Relevance

Type 1 diabetes is an unavoidable, life-long illness with no known cure and an imperfect treatment from which more than 15,000 new children will begin to suffer in the next year. The disease results from incorrect function of the patient's immune system and thus therapies that target and correct disordered immunity must be sought. In this proposal, we will develop a roadmap for the innovative application of the regulatory power of B lymphocytes to overcome this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK090146-03
Application #
8433472
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2011-05-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$144,600
Indirect Cost
$10,711
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhao, Gaoping; Moore, Daniel J; Kim, James I et al. (2014) An immunosufficient murine model for the study of human islets. Xenotransplantation 21:567-73
Weitkamp, Jörn-Hendrik; Rosen, Michael J; Zhao, Zhiguo et al. (2014) Small intestinal intraepithelial TCR??+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis. PLoS One 9:e99042
DiGiandomenico, Antonio; Veach, Ruth Ann; Zienkiewicz, Jozef et al. (2014) The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation. PLoS One 9:e110183
Romano-Keeler, Joann; Moore, Daniel J; Wang, Chunlin et al. (2014) Early life establishment of site-specific microbial communities in the gut. Gut Microbes 5:192-201
Elizer, Sydney K; Marshall, Andrew F; Moore, Daniel J (2014) Dysregulation of T lymphocyte proliferative responses in autoimmunity. PLoS One 9:e106347
Mouledoux, Jessica H; Albers, Erin L; Lu, Zengqi et al. (2014) Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients. Pediatr Transplant 18:197-203
Weitkamp, Jorn-Hendrik; Koyama, Tatsuki; Rock, Michael T et al. (2013) Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut 62:73-82
Liu, Yan; Major, Amy S; Zienkiewicz, Jozef et al. (2013) Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc 2:e000093
Shoemaker, Ashley H; Zienkiewicz, Jozef; Moore, Daniel J (2012) Clinical assessment of HNF1A and GCK variants and identification of a novel mutation causing MODY2. Diabetes Res Clin Pract 96:e36-9
Lin, Qing; Liu, Yan; Moore, Daniel J et al. (2012) Cutting edge: the "death" adaptor CRADD/RAIDD targets BCL10 and suppresses agonist-induced cytokine expression in T lymphocytes. J Immunol 188:2493-7

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