University of Missouri School of Medicine MU Health School of Medicine

Kathy Sharpe-Timms, PhD, HCLD

Research

Introduction

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I simultaneously established my research laboratory and the assisted reproduction embryology laboratories at the University of Missouri – Columbia in July of 1990. That fall I hired a Research Specialist named Randy Zimmer, who continues to be an invaluable part of our team today. Young and enthusiastic, we established our research program in ~500 sq. ft. of laboratory space in the Health Science Center and our embryology laboratories in the adjoining University Hospital Same Day Surgery Suite.

I brought forward my emerging research interests in endometriosis, which were fostered during my postdoctoral fellowship under the guidance of Michael W. Vernon, Ph.D. at the University of Kentucky. Endometriosis is a gynecological disease causing pain and infertility in women of reproductive age. Presently, diagnosis of endometriosis requires costly, invasive surgery and there is no known cure for endometriosis. The mechanisms involved with the pathogenesis and pathophysiologies of endometriosis are poorly understood.

Over the years, endometriosis has been the mainstay of our research, primarily investigating the pathogenesis of endometriosis. Numerous postdoctoral fellows and graduate,

undergraduate and medical students (see People section) joined us in our quest to identify mechanisms associated with the pathogenesis of endometriosis in order to develop a non-surgical diagnostic marker for this enigmatic disease.

More recently our focus has broadened to include the pathophysiologies of endometriosis, in particular studies of the mechanisms causing reduced fecundity. These ongoing studies have identified mechanisms of ovarian dysfunction and anomalies in oocyte quality and embryo development. We are now modulating these mechanisms in to reduce the subfertility associated with endometriosis.

We strive to translate our basic science discoveries into medical practice to assist women suffering from endometriosis and other reproductive diseases. We hope to encourage the next generation of scientists to hold true to their aspirations and go boldly forward into the unknown.

Lab

New information coming soon.

Goals

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The long term goals of our research are to unravel root and proximal mechanisms by which endometriosis decreases fecundity. By understanding these mechanisms, novel, targeted approaches for restoration of fertility may be developed. Such approaches are paramount to shift from surgical or chemical obliteration of lesions or repeated attempts at IVF. Comparing data from a rat model to data from women will facilitate mechanistic studies as to how endometriosis reduces fecundity, provide an avenue to test safety and efficacy of new therapeutic approaches, and assist rapid of translation of data into knowledge of human endometriosis.

Current Projects

Our novel discoveries have shown that eutopic endometrial tissue, retrogradely shed menstrual tissue and ectopic endometriotic lesions from women with endometriosis, but not women without endometriosis, produce a uniquely glycosylated form of haptoglobin (eHp). eHp binds to peritoneal macrophages and reduces phagocytic function while eliciting secretion of inflammatory cytokines. This feed forward loop between the endometrium/endometriotic lesions and immune cells in women with endometriosis helps explain why only some women get endometriosis while most women have retrograde menstruation. Mechanisms to block eHp production and/or function may be developed into novel therapeutic approaches to prevent endometriosis and reduce or eliminate endometriotic lesions and the pain and subfertility they cause.

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Most recently, our endometriosis research team has discovered that tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) produced by endometriotic lesions and interferes with normal ovarian function, embryo implantation and development and endometrial receptivity for embryo implantation. We are currently modulating TIMP-1 in an animal model for endometriosis and have found that TIMP-1 treatment reduces fecundity in control animals while a TIMP-1 blocking agent restores fecundity in rats with endometriosis.

We are currently exploring how the reproductive anomalies associated with endometriosis are multigenerational. Epigenetic modifications appear to methylate targeted genes and alter their expression thereby affecting in these mechanisms.

 

Publications (since 1990)
  1. Sharpe (Timms) KL, Bertero MC, Vernon MW. Rapid regression of endometriosis by a new gonadotropin-releasing hormone antagonist in rats with surgically induced disease. Prog Clin Biol Res. 1990; 323:449-58. PMID: 2406755
  2. Sharpe (Timms) KL, Bertero MC, Lyon BP, Muse KN, Vernon MW. Follicular atresia and infertility in rats treated with a gonadotropin-releasing hormone antagonist. Endocrinol 1990 Jul;127(1):25-31. PMID: 2113868
  3. Sharpe (Timms) KL, Bertero MC, Vernon MW. Spontaneous and steroid-induced recurrence of endometriosis following suppression by a gonadotropin‑releasing hormone antagonist in the rat. Amer J Obstet Gynecol 1991; 164:187-94. PMID: 1986606
  4. Sharpe (Timms) KL, Zimmer RL, Khan RS, Penney LL. Proliferative and morphogenic changes induced by the co-culture of uterine and peritoneal cells: A cell culture model for endometriosis. Fertil Steril 1992; 58:1220-9. PMID: 1459275
  5. Sharpe (Timms) KL, Vernon MW. Polypeptides synthesized and released by rat ectopic uterine tissue differ from those of the uterus in culture. Biol Reprod 1993; 48:1334-40. PMID: 8318587
  6. Moon, CE, Bertero MB, Curry TE, London SN, Muse KN, Sharpe (Timms) KL, Vernon MW. The presence of luteinized unruptured follicle syndrome (LUFS) and altered folliculogenesis in rats with surgically induced endometriosis. Am J Ob Gyn 1993; 169:676- 82. PMID: 8372879
  7. Sharpe (Timms) KL, Zimmer RL, Griffin WT, Penney LL. Polypeptides synthesized and released by human endometriosis tissue differ from those of the uterine endometrium in culture. Fertil Steril 1993; 60(5):839-51. PMID: 7693516
  8. Sharpe-Timms KL, Bruno PL, Penney LL, Bickel JT. Immunohistochemical localization of granulocyte-macrophage colony stimulating factor (GM-CSF) in matched endometriosis and endometrial tissues. Am J Ob Gyn 1994; 171:440-5. PMID: 8092224
  9. Wright JA and Sharpe-Timms KL. Gonadotropin-releasing hormone agonist (GnRHa) therapy reduces postoperative adhesion formation and reformation following adhesiolysis in rat models for adhesion formation and endometriosis. Fertil Steril 1995; 63:1094-100. PMID: 7720924
  10. Sharpe-Timms KL, Penney LL, Zimmer RL, Wright JA, Zhang Y, Surewicz KS. Partial purification and amino acid sequence analysis of endometriosis protein-II (ENDO-II) reveals homology with tissue inhibitor of metalloproteinases-1 (TIMP-1). J Clin Endocrin Metab 1995; 80: 3784-7. PMID: 8530636
  11. Osteen KG, Bruner KL, Sharpe-Timms KL. Steroids and growth factor regulation of matrix metalloproteinases expression and the disease endometriosis. Sem Reprod Endocrin 1996; 14:247-255. PMID: 8885055
  12. Sharpe-Timms KL. Basic Research in Endometriosis. Obstet Gynecol Clin North Am. 1997 Jun;24(2):269-90. Review. PMID: 9163767
  13. Sharpe-Timms KL, Piva M, Ricke EA, Surewicz K, Zhang YL, Zimmer RL. Endometriotic lesions synthesize and secrete a haptoglobin-like protein. Biol Reprod 1998; 58:988-94. PMID: 9546730
  14. Sharpe-Timms KL, Keisler LW, McIntush EW, Keisler DH. Tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations are attenuated in peritoneal fluid and sera of women with endometriosis and restored in sera by gonadotropin-releasing hormone agonist (GnRHa) therapy. Fertil Steril 1998; 69(6): 1128-34. PMID: 9627304
  15. Sharpe-Timms KL, Zimmer RL, Jolliff WJ, Wright JA, Nothnick WB, Curry TE. Gonadotropin-releasing hormone agonist (GnRHa) therapy alters activity of plasminogen activators (PA), matrix metalloproteinases (MMP) and of their inhibitors (PAI and MMPI) in rat models for adhesion formation and endometriosis: potential GnRHa-regulated mechanisms reducing adhesion formation. Fertil Steril 1998; 69(5):916-23. PMID: 9591503
  16. Piva M, Sharpe-Timms KL. Peritoneal endometriotic lesions differentially express a haptoglobin-like gene. Molecular Human Reprod 1999; 5: (1):71-78. PMID: 10050665
  17. Sharpe-Timms KL, Glasser S. Models for the study of uterine receptivity for blastocyst implantation. Seminars in Reprod Endocrin 1999; 17:107-15. Review. PMID: 10406080
  18. Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differential in vivo expression and localization of endometriosis protein-I (ENDO-I), a haptoglobin homologue, in endometrium and endometriotic lesions. Human Reproduction, 2000; 15(10):2180-5. PMID: 11006195
  19. Cox KE, Sharpe-Timms KL, Kamiya N, Saraf M, Donnelly KM, Fazleabas AT. Differential regulation of stromelysin–1 (matrix metalloproteinase-3) and matrilysin (matrix metalloproteinase-7) in baboon endometrium. J Soc Gynecol Invest, 2000; 7:242-8. PMID: 10964024
  20. Piva M, Horowitz GM, Sharpe-Timms KL. Interleukin-6 differentially stimulates haptoglobin production by peritoneal and endometriotic cells in vitro: a model for endometrium-peritoneum interaction in endometriosis. J Clin Endocrin Metab 2001; 86:2553-61. PMID: 11397854 [Selected for publication in special June 2001 issue devoted, in part, to the theme of The Endocrine Society Annual Meeting, “Hormones and Reproductive Health.”]
  21. Cox KE, Piva M, Sharpe-Timms KL. Differential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions as compared to endometrium. Biol Reprod 2001; 65: 1297-303. PMID: 11566756
  22. Sharpe-Timms KL. Endometrial anomalies in women with endometriosis. Ann NY Acad Sci, 2001; 934:131-47. PMID: 11594534
  23. Sharpe-Timms KL, Cox, K. Paracrine regulation of matrix metalloproteinase expression in endometriosis. Ann NY Acad Sci 2002; 955:147-56. PMID: 11949944
  24. Sharpe-Timms KL. Using rats as a research model for the study of endometriosis. Ann NY Acad Sci 2002; 955:318-27. PMID: 11949958
  25. Barrier BF, Sharpe-Timms KL. Expression of soluble adhesion molecules in sera of women with stage III and IV endometriosis. J Soc Gyn Invest 2002; 9:98-101. PMID: 11963839
  26. Sharpe-Timms KL, Zimmer RL, Ricke EA, Piva MA, Horowitz GM. Endometriotic haptoglobin binds peritoneal macrophages and alters their function in endometriosis. Fertil Steril; 2002; 78:810-819. PMID: 12372461 [Selected for Publication in Special Endometriosis Issue].
  27. Piva MA, Moreno I, Sharpe-Timms KL. Glycosylation and over-expression of endometriosis-associated peritoneal haptoglobin. Glycoconj J 2003; 19(1):33-41. PMID: 12652078
  28. Sharpe-Timms KL, Young SL. Understanding Endometriosis: the key to successful therapeutic management. Fertil Steril 2004; 81(5): 1201-3. PMID: 15136076
  29. Sutovsky P, Manandhar G, Laurincik J, Letko J, Camano JN, Day BN, Lai L, Prather RS, Sharpe-Timms KL, Zimmer R, Sutovsky M. Expression and proteasomal degradation of the major vault protein (MVP) in mammalian oocytes and zygotes. Reproduction. 2005; 129(3):269-82:1-15. PMID: 15749954. Selected for Cover Image.
  30. Sharpe-Timms, KL. Haptoglobin expression by shed endometrial tissue fragments found in peritoneal fluid. Fertil Steril 2005; 84(1):22-30:35-7. PMID: 16009149
  31. Sharpe-Timms, KL. Defining endometrial cells: the need for improved identification at ectopic sites and characterization in eutopic sites for developing novel methods of management for endometriosis. Fertil Steril 2005; 84(1):35-7; discussion 38-9:22-30. PMID: 16009152
  32. Barrier BF, Kendall BS, Sharpe-Timms KL, Kost ER. Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma. Gynecol Oncol. 2006;103(1):25-30. Epub 2006 Mar 10. PMID: 16530254
  33. Barrier BF, Kendall BS, Ryan CE, Sharpe-Timms KL. HLA-G is expressed by the glandular epithelium of peritoneal endometriosis but not in eutopic endometrium. Hum Reprod. 2006; 21(4):864-9. Epub 2005 Nov 25.
  34. Hegedűs B, Marga F, Jakab K, Sharpe-Timms KL, Forgács G. The interplay of cell-cell and cell-matrix interactions in the invasive properties of brain tumors. Biophysical J 2006; 91:1-9. PMID: 16829558
  35. Cameo P, Szmidt M, Strakova Z, Mavrogianis P, Sharpe-Timms KL, Fazleabas AT. Decidualization regulates the expression of the endometrial chorionic gonadotrophin receptor in the primate. Biol Reprod 2006; 75:681-9.PMID: 16837644
  36. Stilley JAW, Woods-Marshall R, Sutovsky M, Sutovsky P, Sharpe-Timms KL. Reduced fecundity in female rats with surgically-induced endometriosis and in their daughters: A potential role for Tissue Inhibitors of Metalloproteinase 1. Biol Reprod, 2009; 80:649-656. PMID: 19020297
  37. Pelch KE, Schroder AL, Kimball PA, Sharpe-Timms KL, Davis JW, Nagel SC. Aberrant gene expression profile in a mouse model of endometriosis mirrors that observed in women. Fertil Steril 2010; 93 (5):1615-1627. PMID: 19473656
  38. Sharpe-Timms KL.Haptoglobin expression in endometrioid adenocarcinoma of the uterus. Reproductive Sciences.  Reprod Sci. 2010; 17:47-55. PMID: 19801537
  39. Sharpe-Timms KL, Nabli H, Zimmer RL, Birt JA, Davis JW. Inflammatory cytokines upregulate human endometrial haptoglobin production in women with endometriosis. Hum Reprod 2010; 25:1241-50. PMID: 20176595
  40. Stilley JAW, Birt JA, Nagel SC, Sutovsky M, Sutovsky P, Sharpe-Timms KL. Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod 2010; 83:185–194. Epub 21April 2010. PMID: 20410455
    Article highlighted in Eunice Kennedy Shriver National Institute of Child Health and Human Development Spotlight
    .  Endometriosis Awareness Month & NICHD Research.  http://www.nichd.nih.gov/news/resources/spotlight/pages/032912-endometriosis.aspx
  41. Pelch KE, Sharpe-Timms KL, Nagel SC. Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. J Visualized Exp (JoVE). January 6, 2012 Article 3396. DOI: 10.3791/3396.
  42. Stilley JA, Sharpe-Timms KL. TIMP1 contributes to ovarian anomalies in both an MMP-dependent and -independent manner in a rat model. Biol Reprod 2012; 86:47, 1-10. Epub 2 Nov 2011. PubMed PMID: 22053095.
  43. Stilley JA, Birt JA, Sharpe-Timms KL. Cellular and molecular basis for endometriosis-associated infertility. Cell Tissue Res. 2012; 349 (3): 849-862. Epub 3 Feb 2012. PubMed PMID: 22298022
  44. Sharpe-Timms KL. Endometriosis: Sampson’s Theory, the rest of the story. World Endometriosis Society eJournal 2012; February 22
  45. Birt JA, Nabli H, Stilley JA, Windham EA, Frazier SR, Sharpe-Timms KL. Elevated peritoneal fluid TNF-α incites ovarian early growth response factor 1 expression and downstream protease mediators: a correlation with ovulatory dysfunction in endometriosis. Reprod Sci. 2013 May;20(5):514-23. doi: 10.1177/1933719113477479. Epub 2013 Feb 20. PubMed PMID: 23427178. 
  46. Johnson NP, Hummelshoj L, the World Endometriosis Society Montpellier Consortium (Abrao MS, Adamson GD, Allaire C, Amelung V, Andersson E, Becker C, Birna Árdal KB, Bush D, de Bie B, Chwalisz K, Critchley H, D’Hooghe T, Dunselman G, Evers  JLH, Farquhar C, Faustmann T, Forman A, Fourquet J, Fraser I, Giudice L, Gordts S, Guidone H, Guo SW, Healy D, Hedon B, Hulkkonen J, Hull L, Hummelshoj L, Johnson NP, Just M, Kiesel L, Lam A, Lynam C, Mettler L, Miller C, North H, Pai R, Petta C, Prentice L, Reilly S, Reis F, Rolla E, Rombauts L, Schweppe KW, Seckin T, Sharpe-Timms KL, Shepperson Mills D, Singh S, Soriano D, Stafford-Bell M, Stratton P, Taylor R, Tsaltas J, Veit J, Vercellini P.  Consensus on current management of endometriosis. Hum Reprod 2013; Hum Reprod. 2013 Jun;28(6):1552-68. doi: 10.1093/humrep/det050. Epub 2013 Mar 25. PubMed PMID: 23528916.
  47. Birt JA, Taylor KH, Davis JW, Sharpe-Timms KL. Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos. Fertil Steril. 2013 Nov;100(5):1436-43. Epub 2013 Aug 15. PMID: 23954358; PMCID: PMC3847911.
    Note: The article was recommended by Faculty of 1000 PRIME: F1000Prime Recommendations, Dissents and Comments for [Birt JA et al., Fertil Steril 2013]. In F1000Prime, 11 Sep 2013; F1000Prime.com/718077638.
  48. Becker CM, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. Fertil Steril 2014 doi 10.1016/j.fertnstert.2014.07.709
  49. Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, Giudice LC, Stratton P, Adamson GD, Becker CM, Zondervan KT, Missmer SA; WERF EPHect Working Group. World Endometriosis Research Foundation Endometriosis phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril. 2014 Sep 18. pii: S0015-0282(14)01885-8. doi: 10.1016/j.fertnstert.2014.07.1244. [Epub ahead of print] Review. PubMed PMID: 25256930.
  50. Rahmioglu N, Fassbender A, Vitonis AF, Tworoger SS, Hummelshoj L, D'Hooghe TM, Adamson GD, Giudice LC, Becker CM, Zondervan KT, Missmer SA; for the WERF EPHect Working Group. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research. Fertil Steril. 2014 Sep 17. pii: S0015-0282(14)01835-4. doi: 10.1016/j.fertnstert.2014.07.1208. [Epub ahead of print] Review. PubMed PMID: 25256929.
  51. Fassbender A, Rahmioglu N, Vitonis AF, Viganò P, Giudice LC, D'Hooghe TM, Hummelshoj L, Adamson GD, Becker CM, Missmer SA, Zondervan KT; for the WERF EPHect Working Group. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue Collection, processing, and storage in endometriosis research. Fertil Steril. 2014 Sep 17. pii:S0015-0282(14)01836-6. doi: 10.1016/j.fertnstert.2014.07.1209. [Epub ahead of print] Review. PubMed PMID: 25256928.
  52. Casper RF. New tools for enhancing collaborative endometriosis research. Fertil Steril 2014 doi: 10.1016/j.fertnstert.2014.07.1211
    This issue of Fertility and Sterility contains four articles by the World Endometriosis Research Foundation whose present objective is global standardization of the collection of phenotypic data and biological samples, designated as the Endometriosis Phenome and Biobanking Harmonisation Project. The aim is to facilitate large-scale international, multicenter trials that are robust, and will result in biomarker and treatment targets to advance research in endometriosis.
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