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Seth A. Brooks, PhD

Title(s):
Associate Professor of Medicine
Associate Professor of Microbiology and Immunology

Department(s):
Medicine
Microbiology and Immunology

Education:
University of. Pennsylvania, BA Philosophy 1989
University of California, Berkeley, PhD Integrative Biology 1996

Programs:
Immunology Program

Websites:
http://dms.dartmouth.edu/microbio/

Contact Information:

VA Medical Center
Research 151
215 North Main St
White River Junction VT 05009

Phone: 802-295-9363 X5616
Email: seth.brooks@dartmouth.edu


Professional Interests:

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, Crohn¡¦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.


Cancer Immunotherapy

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.

Grant Information:

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

Courses Taught:

Clinical Review of Immunology


Selected Publications:

 

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
Goodson WH 3rd, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci A, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams G, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi AI, Klaunig JE, Vondraček J, Raju J, Roman J, Wise JP Sr, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D'Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar PK, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Sing Leung P, Nangia-Makker P, Cheng QS, Robey RB, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Abd Hamid R, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell WK, Engstrom W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z
Carcinogenesis. 2015 Jun;36 Suppl 1:S254-96. doi: 10.1093/carcin/bgv039.
PMID: 26106142

Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.
Brooks SA, Blackshear PJ
Biochim Biophys Acta. 2013 Jun-Jul;1829(6-7):666-79. doi: 10.1016/j.bbagrm.2013.02.003. Epub 2013 Feb 18.
PMID: 23428348

Cullin 4B is recruited to tristetraprolin-containing messenger ribonucleoproteins and regulates TNF-α mRNA polysome loading.
Pfeiffer JR, Brooks SA
J Immunol. 2012 Feb 15;188(4):1828-39. doi: 10.4049/jimmunol.1102837. Epub 2012 Jan 18.
PMID: 22262661

Functional interactions between mRNA turnover and surveillance and the ubiquitin proteasome system.
Brooks SA
Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):240-52. doi: 10.1002/wrna.11. Epub 2010 May 14.
PMID: 21935888

A flexible approach to studying post-transcriptional gene regulation in stably transfected mammalian cells.
Nichols RC, Botson J, Wang XW, Hamilton BJ, Collins JE, Uribe V, Brooks SA, Zan M, Rigby WF
Mol Biotechnol. 2011 Jul;48(3):210-7. doi: 10.1007/s12033-010-9360-8.
PMID: 21153715

CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes.
Pfeiffer JR, McAvoy BL, Fecteau RE, Deleault KM, Brooks SA
Mol Cell Biol. 2011 Jan;31(2):277-86. doi: 10.1128/MCB.00775-10. Epub 2010 Nov 15.
PMID: 21078874

Extracellular signal-regulated kinase regulation of tumor necrosis factor-alpha mRNA nucleocytoplasmic transport requires TAP-NxT1 binding and the AU-rich element.
Skinner SJ, Deleault KM, Fecteau R, Brooks SA
J Biol Chem. 2008 Feb 8;283(6):3191-9. Epub 2007 Nov 29.
PMID: 18048358

View more publications on PubMed