This proposal details a 5 year training program for the development of an academic career in the study of B cell developmental biology and immune tolerance. The PI has joined the laboratory of Fred Alt to study B cell receptor editing and the regulation of immunoglobulin light chain rearrangement, and plans to utilize the rigorous scientific environment in the Alt to develop expertise in cutting edge molecular tools. The PI plans to then utilize these tools as he becomes an independent investigator to dissect the mechanistic and molecular underpinnings of clinically relevant problems in B cell immunology. The PI is currently a Clinical Fellow in Medicine conducting research under the direction of Dr. Frederick Alt (mentor) and Dr. Frank Austen (co-mentor). His research focus involves the characterization of a subpopulation of B cells that he recently found to rearrange the immunoglobulin lambda light chain (Ig() locus in mesenteric lymph node B cells. In the proposed plan, the PI will characterize this population of peripheral editing cells (Aim 1) and develop mouse models to investigate this Ig( locus rearrangement activity with respect to immunological tolerance to the gut environment (Aim 2).
In Aim 3, he will pursue studies to elucidate the molecular mechanisms involved in regulation of immunoglobulin light chain gene rearrangements. Together, results from this proposal will advance our understanding of the mechanisms of B cell development, antibody specificity modulation and regulation of DNA accessibility to V(D)J rearrangement machinery. Moreover, these studies may aid the understanding of peripheral B cell receptor editing in allergic and/or inflammatory disease processes. The mentor is an eminent scientist in the field with over 100 established trainees and is fully focused on his current laboratory program. The co-mentor is also an eminent scientist with expertise in mouse models of hypersensitivity diseases who will aid in the candidates career development. Advisory committee members are exceptionally outstanding, respected immunologists who will also oversee the progress of this proposal and provide critique on the methods and interpretation of results at scheduled meetings and informally. The research will take place within the highly collaborative environment of the Immune Disease Institute/Program for Cellular and Molecular Medicine at the Children's Hospital Boston. The PI will also benefit from the environment of his home institution, the Inflammation and Allergic Diseases Research Section at BWH. Both of these institutions are committed to providing the necessary resources and training to help the primary investigator establish an independent career. Failure of our immune system to develop tolerance food and "good" bacteria leads to disease. Studies to determine the mechanism of tolerance to these entities will be critical to designing new therapies for prevention and treatment of food allergy and inflammatory bowel disease.

Public Health Relevance

Failure of our immune system to develop tolerance food and good bacteria leads to disease. Studies to determine the mechanism of tolerance to these entities will be critical to designing new therapies for prevention and treatment of food allergy and inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI089972-05
Application #
8681303
Study Section
Transplantation Biology &Immunology-2 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Wesemann, Duane R; Portuguese, Andrew J; Meyers, Robin M et al. (2013) Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 501:112-5
Oksenych, Valentyn; Alt, Frederick W; Kumar, Vipul et al. (2012) Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair. Proc Natl Acad Sci U S A 109:2455-60
Zha, Shan; Guo, Chunguang; Boboila, Cristian et al. (2011) ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 469:250-4
Wesemann, Duane R; Magee, Jennifer M; Boboila, Cristian et al. (2011) Immature B cells preferentially switch to IgE with increased direct S? to S? recombination. J Exp Med 208:2733-46