The extracellular matrix contributes to mechanotransduction in uterine fibroids.

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2014

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Abstract

The role of the extracellular matrix (ECM) and mechanotransduction as an important signaling factor in the human uterus is just beginning to be appreciated. The ECM is not only the substance that surrounds cells, but ECM stiffness will either compress cells or stretch them resulting in signals converted into chemical changes within the cell, depending on the amount of collagen, cross-linking, and hydration, as well as other ECM components. In this review we present evidence that the stiffness of fibroid tissue has a direct effect on the growth of the tumor through the induction of fibrosis. Fibrosis has two characteristics: (1) resistance to apoptosis leading to the persistence of cells and (2) secretion of collagen and other components of the ECM such a proteoglycans by those cells leading to abundant disposition of highly cross-linked, disoriented, and often widely dispersed collagen fibrils. Fibrosis affects cell growth by mechanotransduction, the dynamic signaling system whereby mechanical forces initiate chemical signaling in cells. Data indicate that the structurally disordered and abnormally formed ECM of uterine fibroids contributes to fibroid formation and growth. An appreciation of the critical role of ECM stiffness to fibroid growth may lead to new strategies for treatment of this common disease.

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10.1155/2014/783289

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Leppert, Phyllis C, Friederike L Jayes and James H Segars (2014). The extracellular matrix contributes to mechanotransduction in uterine fibroids. Obstet Gynecol Int, 2014. p. 783289. 10.1155/2014/783289 Retrieved from https://hdl.handle.net/10161/12662.

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Scholars@Duke

Phyllis Carolyn Leppert

Professor Emeritus of Obstetrics and Gynecology

My Research Interest is the Molecular Biology and development of medical treatments for Uterine fibroids or leiomyomas these are extremely common benign tumors of reproductive age women and are a leading cause of hysterectomy as well as significant morbidity. In addition there are reported racial differences in growth characteristics of fibroids. New studies indicate that uterine fibroids are present in 80% of women of African descent and up to 70-77% in women of European descent. Associated with uterine bleeding and pelvic pain and pressure, they were traditionally thought to be due to the proliferation of smooth muscle cells. However, recent work based on micro-array and on epidemiological data provides evidence that these growths are caused by the accumulation of secretion by the leiomyocyte of altered components of the extracellular matrix, especially collagen. Thus the etiology of these tumors is related to fibrosis in other tissues. Progress has been made in identify the pathways leading to the accumulation of altered extracellular matrix in these tumors. The most important are 1) fibroids are similar in matrix composition to skin keloids, a type of altered wound healing. 2) Progesterone partial antagonists cause significant reduction in the size of uterine fibroids and in reduction of the uterine bleeding associated with them 3) differential gene expression demonstrates defined molecular subtypes. Translational research in my laboratory focuses on the thrombospondin 1 as a modulator of angiogenesis in uterine tumors and on the initiation of the differentiation of the myocyte to leiomyocyte leading to the altered secretion of collagen and other components of the matrix and to the role of mechanotransduction in the etiology of uterine fibroids. My research also focuses on Clinical Trials of drug treatment regimens for fibroids.

Jayes

Friederike Luking Jayes

Assistant Professor in Obstetrics and Gynecology

I am trained as a Reproductive Physiologist with basic and translational research experience in multidisciplinary, collaborative settings. Improving women’s health requires the understanding of the underlying pathophysiology and the development of effective treatments. My current research focuses on uterine fibroids. These non-cancerous, often bulky and firm tumors have a major impact on women’s health, on quality of life and on health cost. They are a leading cause for hysterectomies. Medical treatment options mostly target hormone levels and are either short-lived or have significant side effects. The etiology of this disease remains poorly understood. Our research embraces a new direction in thinking about uterine fibroids. Uterine fibroids are more than neoplasms; they are a fibrotic disease. Abundant extracellular matrix (ECM) is a major component of uterine fibroid tumors and we focus on the production and degradation of collagen within the fibroids, changing the mechanical forces within these tumors leading to changes in stiffness. We are currently testing the local injection of purified collagenase into uterine fibroids. This treatment option can be carried out under ultrasound control, is non-hormonal, and does not require surgery. I also collaborate with Dr. Darlene Taylor at North Carolina Central University (NCCU). She is a chemist who developed a co-polymer drug delivery system that is liquid at room temperature and gels at body temperature. Collagenase (or other anti-fibrotic drugs) injected into fibroids in combination with her co-polymer could extend the localization and activity of the drugs within the treated tumors, allow for lower dosages, and reduce the need for repeat injections.

Another passion of mine is providing guidance and support for the career development of students, postdocs, and faculty and I am dedicated to help increase diversity and equity in the biomedical workforce through mentoring, community building, research, and leadership. My broad educational background and my work experience in clinical and non-clinical academic settings, government institutes, and industry collaborations have given me a useful perspective of diverse pathways to success. I have accumulated a considerable amount of institutional knowledge and interdisciplinary networks to support trainees with a wide variety of backgrounds, working in a range of disciplines on various projects. I stay engaged in this work through my work (a) as the Duke PI of a NIH U01-award investigating components of peer mentoring to enhance racial and ethnic diversity in the biomedical workforce (PROMISE study); (b) as the Co-Director of the Duke Clinical and Translational Science Institute (CTSI) Community of Scholars (CoS); and (c) as part of the leadership team of three K12 career development awards: (1) the Multidisciplinary K12 Urologic Research (KURe) Career Development Program, (2) the Women's Reproductive Health Research Program (WRHR). and (3) the Building Interdisciplinary Research Careers in Women's Health (BIRCWH). The Duke BIRCWH program has partnered with North Carolina Central University (NCCU), a historically black institution (HBCU), since 2002.


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