IMPACT OF MENOPAUSE ON VAGINAL CONNECTIVE TISSUE SUPPORT

更年期对阴道结缔组织支持的影响

• 批准号: 7409148
• 负责人: Pamela A. Moalli
• 金额: $ 26.67万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409148
• 关键词: Animals; Applications Grants; Biochemical; Biological; Biological Assay; Biology; Biomechanics; Biopsy; Cells; Childbirth; Collagen; Complex; Connective Tissue; Data; Deterioration; Development; Discipline of obstetrics; Disease; Doctor of Philosophy; Elastin; Enrollment; Environmental Exposure; Estradiol; Estrogens; Failure; Fascia; Fecal Incontinence; Fibrillar Collagen; Fibroblasts; Frequencies; Genetic; Genital system; Grant; Hormonal; Human; Image; Individual; Inferior; Injury; Lateral; Length; Life; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Medical; Menopause; Metalloproteases; Modeling; Muscle; Observational Study; Operative Surgical Procedures; Organ; Ovariectomy; Pathogenesis; Patients; Pattern; Pelvis; Physiological; Physiology; Play; Postmenopause; Premenopause; Prevalence; Progesterone; Property; Proteins; Ptosis; Rate; Rattus; Recording of previous events; Recurrence; Regulation; Relative (related person); Risk Factors; Role; Sexual Dysfunction; Site; Smooth Muscle; Social isolation; Structure; Supplementation; Surgeon; System; Tensile Strength; Testing; Tetracycline; Tetracyclines; Time; Tissue Procurements; Tissues; United States; Universities; Vagina; Variant; Viscera; Woman; Women' s Health; base; energy density; experience; falls; hormone therapy; human female; human tissue; improved; inhibitor/antagonist; levator ani muscle; middle age; multidisciplinary; pressure; prevent; protein expression; repaired; soft tissue; success; tetracycline CMT-8; urinary

DESCRIPTION (provided by applicant): Loss of the vaginal connective tissue support results in prolapse of the pelvic viscera into the vaginal canal. Prolapse and the sequela of prolapse have a profoundly negative impact on the lives of millions of women. Eleven percent of women in the United States will undergo a major surgical procedure to repair prolapse and 30% require re-operation because of failure (4). Until now, most studies have focused on childbirth as the primary risk factor for developing prolapse; however, the majority of women do not develop prolapse until decades following childbirth indicating that other factors play a role (4-6, 35-38). In this revised grant application, we have collected a multidisciplinary team of experts to study menopause as a risk factor for prolapse by performing a comprehensive analysis of the impact of menopause on the supportive connective tissue of the vagina. In Aims I-1 and 1-2, we propose to compare biopsies of vaginal supportive connective tissue in premenopausal and postmenopausal women not on hormone therapy to test whether a decrease in the ratios of collagen [I/(III + V)] in postmenopausal women not on hormone therapy leads to inferior biomechanical properties and predisposes to prolapse. In addition, we determine whether quantitative changes in the amount of elastin and/or smooth muscle relative to collagen correlate with a deterioration in biomechanics. Finally, in this section of the grant, we ask whether hormone therapy in postmenopausal women improves the structural and biomechanical deficiencies identified in the vaginal connective tissue of postmenopausal women not on hormone therapy. In Aim II-1, we will investigate whether the changes in these structural components of the vaginal connective tissue are due to an alteration in the expression and activity pattern of the connective tissue degrading Matrix Metalloproteinases (MMPs) relative to their endogenous inhibitors (Tissue Inhibitors of MMPs, TIMPs). We measure the expression and activity of individual metalloproteinases using biochemical assays and net proteolytic activity in tissue using substrate degradation assays. The mechanism of regulation of MMP/TIMP expression by 17-beta-estradiol +/- progesterone is studied, in parallel, in cells derived from the supportive vaginal connective tissue in culture. Because of the limitations inherent in studies on human tissues, we use a rat model in Aims III-1 and 111-2, to determine whether supplementation with 17-beta-estradiol, 17-beta-estradiol and progesterone or the MMP inhibitor - chemically modified tetracycline-8, prevents the deterioration in the biomechanical properties of the vaginal connective tissue that occur following a surgically induced menopause in middle aged rats. We have exciting preliminary data to support each of the Aims outlined in the study. We believe that the results of this revised grant proposal will elucidate an important mechanism that predisposes women to vaginal wall prolapse and will ultimately contribute to the development of preventative strategies to treat this common and debilitating, yet vastly understudied disease.

描述（由申请人提供）：阴道结缔组织支撑的丧失导致盆腔内脏脱垂到阴道管中。脱垂及其后遗症对数百万女性的生活产生深远的负面影响。 11% 的美国女性将接受重大手术来修复脱垂，30% 的女性因失败而需要再次手术 (4)。到目前为止，大多数研究都将分娩视为脱垂的主要危险因素。然而，大多数女性直到分娩后数十年才会出现脱垂，这表明其他因素也发挥了作用 (4-6, 35-38)。在这份修订后的拨款申请中，我们召集了一个多学科专家团队，通过对更年期对阴道支持性结缔组织的影响进行全面分析，将更年期作为脱垂的危险因素进行研究。在目标 I-1 和 1-2 中，我们建议比较绝经前和未接受激素治疗的绝经后女性的阴道支持性结缔组织活检，以测试未接受激素治疗的绝经后女性胶原蛋白 [I/(III + V)] 比例的下降是否会导致生物力学特性较差并容易发生脱垂。此外，我们还确定弹性蛋白和/或平滑肌相对于胶原蛋白的量的定量变化是否与生物力学的恶化相关。最后，在拨款的这一部分，我们询问绝经后妇女的激素治疗是否可以改善未接受激素治疗的绝经后妇女阴道结缔组织中发现的结构和生物力学缺陷。在目标 II-1 中，我们将研究阴道结缔组织这些结构成分的变化是否是由于结缔组织降解基质金属蛋白酶 (MMP) 相对于其内源性抑制剂（MMP 的组织抑制剂，TIMP）的表达和活性模式的改变所致。我们使用生化测定来测量单个金属蛋白酶的表达和活性，并使用底物降解测定来测量组织中的净蛋白水解活性。在培养的支持性阴道结缔组织衍生的细胞中，同时研究了 17-β-雌二醇 +/- 孕酮调节 MMP/TIMP 表达的机制。由于人体组织研究固有的局限性，我们在 Aims III-1 和 111-2 中使用大鼠模型，以确定补充 17-β-雌二醇、17-β-雌二醇和黄体酮或 MMP 抑制剂 - 化学修饰的四环素-8 是否可以防止中年手术引起的绝经后阴道结缔组织生物力学特性的恶化。 老鼠。我们有令人兴奋的初步数据来支持研究中概述的每个目标。我们相信，这项修订后的拨款提案的结果将阐明导致女性阴道壁脱垂的重要机制，并最终有助于制定预防策略来治疗这种常见且令人衰弱但尚未充分研究的疾病。

项目成果

Tensile properties of commonly used prolapse meshes.

• DOI: 10.1007/s00192-008-0781-x
• 发表时间: 2009-07
• 期刊: INTERNATIONAL UROGYNECOLOGY JOURNAL
• 影响因子: 1.8
• 作者: Jones, Keisha A.;Feola, Andrew;Meyn, Leslie;Abramowitch, Steven D.;Moalli, Pamela A.
• 通讯作者: Moalli, Pamela A.

Regulation of MMP-1 by sex steroid hormones in fibroblasts derived from the female pelvic floor.

女性盆底成纤维细胞中性类固醇激素对 MMP-1 的调节。

• DOI: 10.1016/j.ajog.2006.12.019
• 发表时间: 2007
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Zong,Wenjun;Zyczynski,HalinaM;Meyn,LeslieA;Gordy,SusanC;Moalli,PamelaA
• 通讯作者: Moalli,PamelaA

Repetitive mechanical stretch increases extracellular collagenase activity in vaginal fibroblasts.

• DOI: 10.1097/spv.0b013e3181ed30d2
• 发表时间: 2010-09-01
• 期刊: Female pelvic medicine & reconstructive surgery
• 影响因子: 1.6
• 作者: Zong W;Jallah ZC;Stein SE;Abramowitch SD;Moalli PA
• 通讯作者: Moalli PA

The amount and activity of active matrix metalloproteinase 13 is suppressed by estradiol and progesterone in human pelvic floor fibroblasts.

人盆底成纤维细胞中活性基质金属蛋白酶 13 的量和活性受到雌二醇和孕酮的抑制。

• DOI: 10.1095/biolreprod.108.072462
• 发表时间: 2009
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Zong,Wenjun;Meyn,LeslieA;Moalli,PamelaA
• 通讯作者: Moalli,PamelaA