Thomas L. Brown, Ph.D. Associate Professor Address: 042 Biological Sciences Building Phone: (937) 775-3809 E-mail: thomas.l.brown@wright.edu University of Cincinnati, 1993

The loss of TGFb in mice results in multifocal lymphocyte infiltration, autoimmune disease and implantation defects. Immune tolerance is tightly regulated by apoptosis and is essential in preventing autoimmune disease. We are currently analyzing the biochemical and molecular signaling mechanisms to determine how neoantigens contribute to autoimmune disease in these mice, which is a model of the human autoimmune diseases Sjogren's Syndrome and Systemic Lupus Erythematosus.

Tumor resistance occurs when genetic alterations in tumor suppressor genes allow certain cells to become resistant to the normal induction of apoptosis and is often accompanied by an immunocompromised state. Several components of the TGFb signaling pathway have been identified as tumor suppressors and are mutated in certain tumor cells. Using resistant cell lines, we are analyzing the cellular and molecular mechanisms that regulate sensitivity and promote resistance in the development and progression of cancer.

A final area of investigation involves the signaling mechanisms involved in trophoblast implantation. Studies will examine effects of cytokines and growth factors on placental development, immune suveillance and apoptosis during implantation.

Our understanding of the biochemical, cellular, and molecular events that control lymphopoiesis, apoptosis, and implantation may contribute to future treatments for autoimmunity, cancer, and infertility.

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Selected Publications:

Brown TL, Moulton BC, Swertfeger DK. Witte DP, Harmony JAK (1996) Apolipoprotein J/clusterin expression defines distinct stages of blastocyst implantation in the mouse uterus. Biol Reprod 55:740-747.

Moulton BC, Akcali KC, Ogle TF, Brown TL, Motz J, Khan SA (1997) Control of apoptosis in the uterus during decidualization. Serono Symposia. In: Cell death in reproductive physiology (Tilly JL, Strauss III JF, Tenniswood M, eds), pp 48-66. New York: Springer-Verlag.

Zhou A, Paranjapoe J, Brown TL, Nie H, Naik S, Dong B, Chang A, Trapp B, Fairchild R, Colmenares C, Silverman RH (1997) Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate dependent RNAse L. Embo J 16:6355-6363.

Brown TL, Patil S, Basnett R, Howe P (1998) Caspase inhibitor, BD-fmk, distinguishes TGFbeta-induced apoptosis from growth inhibition. Cell Growth and Diff 9:869-875.

Hocevar BA, Brown TL, Howe PH (1999) TGFbeta induces fibronectin synthesis though a c-Jun N-terminal kinase-dependent, Smad 4 independent pathway. Embo J 18:1345-1356.

Brown TL, Patil S, Cianci CD, Morrow JS, Howe PH (1999) Transforming growth factor beta induces caspase 3-independent cleavage of alphaII-spectrin (alpha-fodrin) coincident with apoptosis. J Biol Chem 274:23256-23262.

Brown TL, Patil S, Howe PH (2000) Analysis of TGF beta-inducible apoptosis (Transforming growth factor-beta protocols). (Howe P, ed)  Meth Mol Biol (Totowa, NJ: Humana Press) 142:149-67.

Patil S, Wildey GM, Brown TL, Choy L, Derynck R, Howe PH (2000) Smad 7 is induced by CD40 and protects WEHI 231 B-lymphocytes from TGFb-induced growth inhibition and apoptosis. J Biol Chem  275:38363-38370.

Smith AN, Carter QL, Kniss DA, Brown TL (2001) Identification of a TGFb-responsive human trophoblast derived cell line. Placenta 22:425-431.

LePoole IC, Sarangarajan R, Zhao Y, Stennett LS, Brown TL, Sheth P, Miki T, Boissy RE (2001) "VITI", a novel gene associated with vitiligo. Pigment Cell Research 14:475-484.

LePoole IC, Brown TL (2001) Identification of altered gene expression associated with pigmentary lesions by differential display analysis. (Nickoloff BJ, ed) Meth Mol Biol (Totowa, NJ: Humana Press)  61:165-179.

Kadakia M, Brown TL, McGorry M, Berberich S (2002) MdmX mediates Smad transactivation. Oncogene 21:8776-8785.

Brown TL (2003) Steroid Hormones. In: Encyclopedia of genetics, 2nd ed (Ness B, ed) Salem Press (in press).

Caserta TM, Smith AN, Gultice AD, Reedy MA, Brown TL (2003) Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties. Apoptosis 8:345-352.
Identified by Lead Discover as in the top 2.5% of breaking scientific publications with significant drug development potential.

Williams ST, April N, Smith AN, Cianci CD, Morrow JS, Brown TL (2003) Identification of the primary caspase 3 cleavage site in alpha II-spectrin during apoptosis. Apoptosis 8:353:361.

Brown TL (2003) Sjögren's syndrome. In: Magill's medical guide, 3rd ed (Irons-George T, ed) Salem Press (in press).

Zhao Z, Brown TL, Kohler H, Müller S (2003) Transmembrane-antibody induced inhibition of cell suicide. Apoptosis 8:631-637.

Selesniemi K, Brown TL (2003) Metafectene transfection in HSG human salivary gland cells. Biontex Inc, Application Note. http://www.biontex.com.

Brown TL (2003) Placenta. In: Magill's medical guide, 3rd ed (Irons-George T, ed) Salem Press (in press).

Selesniemi K, Brown TL (2004) Efficiency of metafectene transfection in a murine placental trophoblast cell line. Biontex Inc, Application Note. http://www.biontex.com.

Brown TL (2004) Q-VD-OPh, a next generation caspase inhibitor. In: International symposium on cell volume and signal transduction (Lauf PK, ed) Dayton: Kluwer (in press).