Karen A. Gould, Ph.D.

Associate Professor

Karen A. Gould, Ph.D.

University of Wisconsin-Madison

Phone: 402-559-2456
Fax: 402-559-7328
Email: kagould@unmc.edu

    • Chair, Genetics, Cell Biology & Anatomy Graduate Program Committee
    • Member, BRTP Graduate Program Committee
    • Associate Member, UNMC Eppley Cancer Center
    • Member, UNMC Center for Nanomedicine and Drug Delivery
    • Instructor in BRTP, GCBA, PAMM and CIP graduate courses

Teaching: Dr. Gould contributes to graduate education by training graduate students, lecturing in multiple graduate courses for graduate and professional students, and supervising 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 are thought to promote lupus by facilitating loss of tolerance and enhancing antibody production. However, the underlying molecular basis for the effects of estrogens on these processes is not well defined. For example, until recently, it was not clear which estrogen receptor, ERa or ERb, mediated these effects. To examine the role of ERa 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, ERa deficiency in (NZB x NZW)F1 mice reduced the level of the estrogen regulated cytokine Ifng. 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 ERa 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 ERa function, most likely within the immune system, may be effective in the prevention and/or treatment of lupus. Our current studies are focused on further delineating the molecular and cellular basis for ERa-mediated estrogen-dependent promotion of lupus.

II. Renal Targeting of Anti-Inflammatory Drugs for the Treatment of Lupus Nephritis. Glomerulonephritis, or lupus nephritis, is an inflammatory kidney disease that is a major cause of morbidity and mortality in lupus patients. Current therapies for lupus include corticosteroids, such as prednisone and dexamethasone, which are often prescribed in combination with cytotoxic, immunosuppressive drugs, such as cyclophosphamide. There are significant toxicity and morbidity associated with these therapies due to their ubiquitous body distribution. While these therapies can slow disease progression and kidney damage to some extent, not all lupus patients respond to these treatments, partially due to the dose limiting adverse events. Progress in developing targeted or molecular-based therapies for lupus has been slow, and the current focus for most targeted therapy involves targeting of specific cells within the immune system to inhibit immune dysregulation. As a novel approach, we are developing kidney-targeted corticosteroid therapy, which will allow sufficient drug concentration in the kidney for inflammation resolution, while limiting the systemic exposure level of corticosteroid.

III. 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 genes encoding estrogen receptors ERa and ERb are silenced in colorectal tumors in both men and women suggests that ERa and ERb plays a critical role in colorectal cancer in both genders. To examine the impact of losing ERa and ERb expression on intestinal tumorigenesis, we crossed ERa and ERb knockout mouse strains with the ApcMin/+ strain, a well established mouse model of colon cancer. ERb deficiency increased the incidence of colon tumors but did not have a significant impact on total tumor multiplicity. By contrast, ERa deficiency was associated with a significant increase in total tumor multiplicity.
Activation of the Wnt/b-catenin pathway is known to accompany both intestinal tumor development in ApcMin/+ mice and colorectal cancers in humans. Data from our laboratory suggest that in the intestinal epithelium of ApcMin/+ mice, ERa deficiency is associated with stabilization of the b-catenin protein, increased nuclear localization of b-catenin, and increased expression of several genes that are targets of the Wnt/b-catenin signal transduction pathway. Our current studies are focused on understanding how ERa deficiency impacts cell proliferation, differentiation and apoptosis in the intestinal epithelium. These investigations will begin to reveal the molecular consequences of ERa deficiency that may accompany colorectal tumorigenesis and may ultimately facilitate the development of novel chemopreventive and chemotherapeutic agents.

IV. Identification of Genetic Modifiers of Apc-Dependent Tumorigenesis. Our previous work has shown that tumor number in ApcMin/+ mice is affected by genetic modifier loci. On the C57BL6/J (B6) strain background, ApcMin/+ mice development, on average significantly more tumors than ApcMin/+ mice obtained from crosses between B6 ApcMin/+ mice and mice from other inbred strains. These observations indicate that some inbred strains carry alleles at loci that inhibit ApcMin-induced tumorigenesis. We postulate that by identifying these loci and gaining insight into how the action of these loci modulates tumorigenesis in ApcMin/+ mice, we will obtain novel information about pathways that either promote or inhibit tumorigenesis. Recently, we identified a locus we named Modifier of Min 5 (Mom5). The Mom5 allele from the 129P2 inbred strain is associated with a 50% reduction in tumor number in ApcMin/+ mice. Current studies are focused on identifying the causative allelic variant underlying the Mom5 locus and the determination of the mechanism underlying the effect of this allelic variation on tumorigenesis. These studies include the focused investigation of the Rint-1 gene. The Rint-1 gene resides at the center of the genetic interval that defines Mom5. Furthermore, we have identified a potentially significant single nucleotide polymorphism between the 129P2 and B6 Rint-1 genes. Thus, Rint-1 currently represents the most promising candidate gene for Mom5.

Publications listed in PubMed

Selected Recent Publications:

  1. Panchanathan, R, Shen R, Gubbels Bupp M, Gould KA, Choubey D. Female and Male Sex hormones Differentially Regulate Expression of Ifi202, an Interferon-inducible Lupus Susceptibility Gene within the Nba2 Interval. Journal of Immunology, 183(11):7031-38, 2009.
  2. Oikarinen SI, Cleveland AG, Cork K, Bynoté KK, Cleveland AG, Rafter JJ, Gustafsson J-Å, Mutanen M, and Gould KA. Genetic Mapping of Mom5, a novel modifier of ApcMin-induced intestinal tumorigenesis. Carcinogenesis 30(9):1591-96, 2009.
  3. Cleveland, AG, Oikarinen SI, Bynoté, KK, Roy, SK, Pitot, HC, Korach, KS, Lubahn, D, Rafter JJ, Gustafsson J-Å, Mutanen M and Gould, KA. Disruption of Estrogen Receptor Signaling Enhances Intestinal Neoplasia in ApcMin/+Mice. Carcinogenesis 30(9):1581-90, 2009.
  4. Harrison-Findik, D.D. and Gould, K.A. Sex Differences and Liver Hepcidin Expression. In Female Hepatology: Impact of female sex against progression of liver disease, Ichiro Shimizu, Editor-in-Chief, Research Signpost, 2009.
  5. Kurz, S. G., Hansen, K. K., McLaughlin, M.T., Shivaswamy, V., Schaffer, B.S., Gould, K.A., McComb, R.D., Meza, J.L. and Shull, J.D. Tissue Specific Actions of the Ept1, Ept2, Ept6 and Ept9 Genetic Determinants of Responsiveness to Estrogens in the Female Rat. Endocrinology 149(8): 3850-9, 2008.
  6. Bynoté, K.K., Hackenberg, J.M., Korach, K.S., Lubahn, D.B. Lane, P.H. and Gould, K.A. Estrogen Receptor Alpha Deficiency Attenuates Autoimmune Disease in (NZB x NZW)F1 Mice. Genes and Immunity, 9(2):137-52, 2008. *One of three "Featured Articles" in this issue.