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Mark R. Boothby, M.D., Ph.D.

Professor of Microbiology and Immunology
Professor of Medicine
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
AA-4214B Medical Center North
Nashville, TN 37232-2363
615-343-1699

Research Specialty

Signaling and gene regulation mechanisms in immune system hematopoietic cells, especially those of B and T lymphoid lineages. Lymphoid lineage cells are the most central means of regulating characteristics of immunity and auto-immunity, and they also are vital in the inflammation and pathophysiology of most of the main disease burden in the US (atherosclerotic vascular disease with heart attacks and strokes, obesity, diabetes, and cancer), The lab seeks to identify new signal transduction, transcription, and chromatin or epigenetic ways in which lymphoid lineage cells are regulated, with active investigations in immunity, auto-immunity (autoimmunity) and the ways in which sustained antibody responses are evoked since antibody levels are crucial in the efficacy of vaccines and are key components in a variety of autoimmune diseases.

Research Description

We investigate mechanisms by which signaling and transcription factors regulate cell growth, differentiation, and survival. The lab dissects these questions through an integration of genetic manipulations, biochemical studies, and analyses of function in immunity.

Potential projects (2013):

1. Investigation of a novel protein cloned in the lab, which enhances the function of a transcription factor central to allergic diseases and asthma. We are using knockout mice deficient in this cofactor, a novel ADP-ribosyltransferase, to explore how this protein impacts signaling to the regulation of programmed cell death, cellular metabolism, B lymphoma pathophysiology (because of connections to a related protein affecting the outcome of lymphocyte cancers), and the impact of this protein on vaccination and immunity to pathogens.

2. Signaling and immune function mediated by the Akt / mTOR axis of serine-threonine kinases. We have identified evidence of an important role for a novel complex involving the kinase mTOR - "mammalian target of rapamycin" (rapamycin being an important immune suppressant drug) - in T cell differentiation and are dissecting molecular mechanisms involved in these findings as well as impact on leukemia development and on immunity, including T cell memory, B cell development and function in models of vaccination and anti-pathogen immunity, and in autoimmunity.

3. Regulation of cytokine gene transcription. Studies of particular excitement at present include working to understand the molecular and epigenetic basis for two processes we have identified for immunological memory as carried by cells in the T helper 2 subset.

One major focus is on the differentiation of naive T helper lymphocytes into activated cells that have acquired effector functions, i.e., the ability to express new genes that orchestrate immune responses. One subset of effector T helper cells is called the Th2 subset. Differentiation into Th2 effectors is driven by the cytokine IL-4, so one major area of study in the lab is the transduction of signals by the IL-4 receptor and the means by which IL-4 regulates gene transcription. We cloned and knocked out a gene encoding a novel protein that enhances IL-4 induction of transcription and pro-survival signaling. Future studies will include determining the biochemical and function roles of this novel transcriptional coregulator.

We recently discovered that memory Th2 cells permit an unexpected flexibility in regulation of the Th1 cytokine gene for IFN-gamma while at the same time retaining commitment to expression of the characteristic Th2 cytokine genes (IL-4, IL-5, and IL-13). We will dissect molecular mechanisms for both flexibility and commitment, using analyses of transcription factor knockouts as well as of chromatin (epigenetic DNA methylation as well as histone modifications).

A second class of effector T cells is known as the Th1 subset, of which a hallmark is the activation of the gene encoding the inflammatory cytokine interferon-gamma. We dicsoveredthat the transcription factor NF-kappaB is particularly important in the Th1 response but not in responses mediated by Th2 cells, and have identified an orderly sequence of molecular events leading to remodeling of the IFN-gamma promoter. Using analyses of chromatin modifications and structure in the interferon gamma locus, we are in the process of determining the mechanisms by which the gene is regulated in primary T helper subsets, memory CD4 cells, and exploring the impact of these processes on differentiation of another autoimmunity-promoting class of T cells (Th17 cells).

Finally, we are in the midst of developing exciting data for both T and B lymphocytes in relation to the signaling pathways described above and dissecting how these pathways impact the generation and persistence of antibody-producing cells and immune memory.

Publications


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