Karen A. Gould, Ph.D.

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Karen A. Gould, Ph.D. Assistant Professor University of Wisconsin-Madison 1996 Phone: (402) 559-2456 Fax: (402) 559-7328 Email: kagould@unmc.edu Associate Member, UNMC Eppley Cancer Center Chair, Genetics, Cell Biology & Anatomy Graduate Committee Instructor in BRTP, GCBA graduate programs
Teaching: Dr. Gould contributes to graduate education by training graduate students, lecturing in multiple graduate courses and surpervising the departmental journal club for students. Dr. Gould also mentors undergraduate interns and summer students in her laboratory through the UNO biotechnology internship program and UNMC summer research fellowship programs.
Research Keywords: molecular genetics; estrogen action; immune function and autoimmunity; tumorigenesis
Research Areas – I. Estrogen receptor alpha regulation of lupus. Estrogens play a significant role in the etiology and progression of lupus, a chronic autoimmune disease affecting an estimated 1.5 million Americans, 90-95% of whom are women. One of the leading causes of morbidity in lupus patients is glomerulonephritis, an inflammation of the kidney resulting from the deposition of immune complexes in glomeruli. Typically, anti-dsDNA IgG antibodies are a major component of these immune complexes, and high levels of serum anti-dsDNA antibodies usually correlate with active renal disease in lupus patients. Anti-dsDNA antibodies in lupus patients develop via epitope spreading, a poorly understood process by which the antibodies that initially breach immunologic tolerance to nucleosomal antigens, evolve over time to obtain anti-dsDNA specificity. Estrogens, acting via the estrogen receptors ERα and ERβ, are thought to promote lupus by facilitating loss of tolerance and enhancing antibody production. However, the developmental and molecular pathways through which estrogens exert these effects have not been defined. To examine the role of ERα in mediating the effects of estrogen in lupus, we have examined the effect of ERa deficiency in a lupus-prone mouse strain. These studies suggest that ERa is a major mediator of estrogen action the (NZB x NZW)F₁ mouse model of lupus. We have shown that ERa promotes the loss of immunologic tolerance to nucleosomal antigens in this model. Furthermore, ERα deficiency in (NZB x NZW)F₁ mice attenuated the subsequent development of anti-dsDNA IgG antibodies, specifically those of the IgG_2a and IgG_2b isotype, which are tightly associated with glomerulonephritis in this model. ERa deficiency in both (NZB x NZW)F₁ females and males was associated with increased survival and diminished anti-dsDNA antibody levels, suggesting that endogenous signaling through ERa also modulates lupus in both genders, although the impact in females is more dramatic. Our studies suggest that ERα promotes lupus development and pathogenesis in this model, at least in part, by attenuating the development of autoantibodies. Furthermore, these data suggest that targeted therapy specifically disrupting ERα function, most likely within the immune system, may be effective in the prevention and/or treatment of lupus. II. Estrogen receptor regulation of intestinal homoestasis and tumorigenesis. Estrogens and estrogen receptors play an important role in the development of colorectal cancer. Much emphasis has been placed on the potential role of estrogens in reducing colorectal cancer risk in women and explaining the gender bias that exists in colorectal cancer incidence. However, the fact that expression of the estrogen receptor a (ERa) gene is silenced in colorectal tumors in both men and women suggests that ERa action plays a critical role in colorectal cancer in both genders. Consistent with these data, both male and female Apc^Min^/+ mice that do not express the ERa gene (ERa ^-/-) develop 50% more tumors than Apc^Min^/+mice that express normal levels of ERa (ERa^+/+). Activation of the Wnt/b-catenin pathway is known to accompany both intestinal tumor development in Apc^Min^/+ mice and colorectal cancers in humans. Data from our laboratory suggest that the expression of several genes encoding proteins involved in Wnt/b-catenin signal transduction are upregulated in the normal intestinal epithelium of ERa ^-/- Apc^Min^/+mice. Activation of this pathway stimulates the activity of Tcf-b-catenin, a protein complex that controls the expression of many genes involved in cancer development. ERa can also physically interact with Tcf proteins; this interaction modulates the ability of ERs and Tcfs to control gene expression. Thus, we hypothesize that ERa deficiency may lead to a modulation of Tcf-b-catenin activity through two distinct mechanisms: activation of Wnt signaling and modulation of Tcf-ER interactions. We are currently testing these hypotheses by examining the effect of ERa deficiency on cytoplasmic Wnt/b-catenin signal transduction and nuclear Tcf-containing complexes in the intestinal epithelium of Apc^Min^/+ mice. These investigations will begin to reveal the molecular consequences of ERa deficiency that may accompany colorectal tumorigenesis. Ultimately, these studies facilitate the development of novel chemopreventive and chemotherapeutic agents.
Publications listed in PubMed Recent Publications: Shull, J. D., Lachel, C.M., Murrin, C.R., Pennington, K.L., Schaffer, B.S., Strecker, T.E. and Gould, K.A. Genetic Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Pituitary Tumorigenesis in a Brown Norway x ACI Intercross. Mammalian Genome, in press. Shull, J.D., Lachel, C.M., Strecker, T.E., Spady, T.J., Tochacek, M., Pennington, K.L., Murrin, C.R., Meza, J.L., Schaffer, B.S., Flood, L.A. and Gould, K.A. Genetic Bases of Renal Agenesis in the ACI Rat: Mapping of Renag1 to Rat Chromosome 14. Mammalian Genome 17(7):751-9, 2006. Gould, K.A., Hansen, K.K., Strecker, T.E., Bynoté, K.K., Peterson, K.A., and Shull, J.D. Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat. Mammalian Genome 17:451-464, 2006. Schaffer, B.S., Lachel, C. M., Pennington, K.L., Murrin, C.R., Strecker, T.E., Tochacek, M., Gould, K.A., Meza, J.L., McComb, R. D., and J.D. Shull. Genetics Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Susceptibity to Mammary Cancer in a Brown Norway x ACI Intercross. Cancer Research 66 (15):7793-7800, 2006. Pandey, J.,^* Gould, K.A.^, McComb, R.D., Shull, J.D., and Wendell,D.L. Localization of Eutr2, a locus controlling susceptibility to DES-induced uterine inflammation and pyometritis, to proximal RNO5 using a congenic rat strain. Mammalian Genome 16 (11): 865-872, 2005. These authors contributed equally Gould, K.A., Pandey, J., Lachel, C.M., Murrin, C.R., J. Pandey, Flood, L.A., Pennington, K.L., Meza, J.L., Wendell, D.L. and Shull, J.D. Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5. Mammalian Genome 16 (11):854-864, 2005. Strecker, T.E., Spady, Schaffer, B.S., Gould, K.A., T.J., Kaufman, A.E., Shen, F., McLaughlin, M.T., Pennington, K.L., Meza, J.L., and Shull, J.D. Genetic Bases of Estrogen-Induced Pituitary Tumorigenesis: Identification of Genetic Loci Determining Estrogen-Induced Pituitary Growth in Reciprocal Crosses between the ACI and Copenhagen Rat Strains. Genetics 169(4):2189-97, 2005. Gould, K.A., Tochacek, M., T.M. Reindl, C.R. Murrin, C.M. Lachel, L.A. Flood, K.L. Pennington, E.A. VanderWoude, J.L. Meza, M.A. Newton, and Shull, J.D. Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat: Mapping of Emca1 and Emca 2 to chromosomes 5 and 18. Genetics 168(4):2113-25, 2004. Lovegrove, A., Sun, S.J., Gould, K.A., Lubahn, D.B., Korach, K.S., and Lane, P.H. Estrogen Receptor Mediated Events Promote Sex-Specific Diabetic Glomerular Hypertrophy. Am J Physiol Renal Physiol. 287(3):F586-91, 2004. Harvell, D.M.E., Buckles, L.K., Gould, K.A., Pennington, K.P., McComb, R.D., and Shull, J.D. Rat strains specific attenuation of estrogen action in the anterior pituitary gland by dietary energy restriction. Endocrine 21:175-83, 2003. Gould, K.A., J.D. Shull, and J. Gorski. DES action in the thymus: inhibition of cell proliferation and genetic variation. Mol. Cell. Endocrinol.170:31-39, 2000. Cormier, R.T., A. Bilger, A.J. Lillich, R.B. Halberg, K.A. Hong, K.A. Gould, N. Borenstein, E.S. Lander, and W.F. Dove. The Mom1 ^AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19: 3182-3192, 2000. Gould, K.A. and E. H. Bresnick. Sequence determinants of DNA binding of the hematopoietic helix-loop-helix transcription factor TAL1: importance of sequences flanking the E-box core. Gene Expression 7: 87-101,1998. Dove, W. F., R. T. Cormier, K. A. Gould, R. H. Halberg, A. J. Merritt, M. A. Newton, and A. R. Shoemaker. The intestinal epithelium and its neoplasms: genetic, cellular, and tissue interactions. Phil. Trans. Roy. Soc. 353: 915-923, 1998. Gould, K. A. and W. F. Dove. Analysis of the Mom1 modifier of intestinal neoplasia in mice. Exptl. Lung Res. 24: 437-453, 1998. Merritt, A. J., K. A. Gould, and W. F. Dove. Polyclonal structure of intestinal adenomas in Apc Min/+ mice with concomitant loss of Apc+ in all tumor lineages. Proc. Natl. Acad. Sci. U.S.A. 94: 13927-13931, 1997. Gould, K. A. and W. F. Dove. Localized action of Min and Mom1 in intestinal neoplasia. Proc. Natl. Acad Sci. U.S.A. 94: 5848-5853, 1997.