Seth A. Brooks, PhD
Associate Professor of Medicine
Associate Professor of Microbiology and Immunology
Microbiology and Immunology
University of. Pennsylvania, BA Philosophy 1989
University of California, Berkeley, PhD Integrative Biology 1996
VA Medical Center
215 North Main St
White River Junction VT 05009
Phone: 802-295-9363 X5616
Posttranscriptional Regulation of Cytokine Expression
The primary focus of our lab is the study of posttranscriptional regulation of TNF-a. TNF-a is a central mediator of inflammation and is critical to the control of infection and activation of immune response. TNF-a overexpression contributes to a number of disease states, including rheumatoid arthritis, Crohn's Disease, and the cachexia associated with AIDS and malignancy.
At the molecular level, TNF-a biosynthesis is largely regulated at the levels of mRNA stability and translation, each of which is orders of magnitude more important than regulation of gene transcription. The importance of TNF-a post-transcriptional regulation in disease was demonstrated with the generation of mice containing a germ line deletion of the TNF-a 3'UTR ARE. Macrophages and T cells from these mice produced 3 to 10 fold more TNF-a protein than their wild-type counterparts. This effect was mediated solely through increased TNF-a mRNA stability and translation. In addition to insights into the regulation of TNF-a biosynthesis, the relevance of these mice was apparent by the spontaneous development of disease pathology indistinguishable from Rheumatoid Arthritis, CrohnÂ¡Â¦s Disease and cachexia.
We are currently studying several proteins involved in TNF-a posttranscriptional regulation, including tristetraprolin (TTP), which regulates TNF-a mRNA stability in monocyte/macrophages. Loss of TTP results in increased TNF-a message stability and a consequent increase in TNF-a protein expression, resulting in inflammatory arthritis and cachexia in TTP (-/-) animals. We are also in the process of characterizing the role of several additional proteins we have identified as specifically interacting with the TNF-a 3'UTR In Vivo.
We are also involved in a larger collaborative effort in cancer immunotherapy. These studies focus on the development and optimization dendritic cell based vaccine strategies.
VA Merit Award - 2008-2011. Mechanism of Action of TTP Mediated TNF-alpha mRNA Decay
VA Merit Award - 2005-2008. Identification of Proteins Mediating Posttranscriptional TNFa Expression
VA MREP Award - 2002-2005. Characterization of the Mechanism of Action of TTP on mRNA Stability
Hitchcock Foundation - 2003. Identification of the In Vivo mRNA Ligands of Tristetraprolin in Monocytes
Arthrits Foundation Post Doctoral Fellowship - 2000-2002. Identification and Characterization of TTP Interacting Proteins
NRSA Post Doctoral Fellowship -1998-2000. Identification of the mRNA ligands bound by hnRNP A2
Clinical Review of Immunology
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.
Cullin 4B is recruited to tristetraprolin-containing messenger ribonucleoproteins and regulates TNF-α mRNA polysome loading.
Functional interactions between mRNA turnover and surveillance and the ubiquitin proteasome system.
A flexible approach to studying post-transcriptional gene regulation in stably transfected mammalian cells.
CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes.
Extracellular signal-regulated kinase regulation of tumor necrosis factor-alpha mRNA nucleocytoplasmic transport requires TAP-NxT1 binding and the AU-rich element.