Elastic Fiber Homeostasis in the Vaginal Wall

描述(由申请人提供)：盆底疾病影响多达三分之一的成年女性。最常见的盆底疾病之一是盆腔器官脱垂，即盆腔器官(膀胱、阴道、宫颈和子宫)通过阴道开口突出。多达11%的女性在有生之年接受过盆腔器官脱垂或尿失禁手术，在美国，每年有超过22.5万例盆腔器官脱垂住院手术，估计每年直接医疗费用超过10亿美元。尽管盆腔器官脱垂的发生有多种机制的假说，但没有一种机制能完全解释这一过程的起源和自然历史。流行病学研究表明，阴道出生和年龄是发生盆腔器官脱垂的两个主要危险因素。在上一次资助期间，我们使用了盆腔器官脱垂的小鼠模型和患有脱垂和不脱垂的女性的组织来研究我们研究计划的总体假设，即阴道壁的支持是通过阴道壁中弹性纤维的合成/组装和降解之间的微妙平衡来维持的。在这一应用中，我们建议建立在这个坚实的基础上，以(我理解弹性纤维结构完整性和蛋白酶激活在 目的：(I)探讨盆腔器官脱垂的发病机制；(Ii)研究新型弹性蛋白微纤维蛋白LTbP4和转化生长因子�信号在盆腔器官脱垂发病机制中的作用；(Iii)利用含或不含雌激素的可注射纳米颗粒水凝胶预防或改善损伤后阴道脱垂的发展。

DESCRIPTION (provided by applicant): Pelvic floor disorders affect up to one-third of adult women. One of the most prevalent pelvic floor disorders is pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening. Up to 11% of women have surgery for pelvic organ prolapse or urinary incontinence in their lifetime and more than 225,000 inpatient surgical procedures for pelvic organ prolapse are performed per year in the United States at an estimated annual direct medical cost of over one billion dollars. Although multiple mechanisms have been hypothesized to contribute to the development of pelvic organ prolapse, none fully explain the origin and natural history of this process. Epidemiologic studies indicate that vaginal birth and aging are the two major risk factors for developing pelvic organ prolapse. During the last funding period, we used mouse models of pelvic organ prolapse and tissues from women with and without prolapse to investigate the overall hypothesis of our research program, namely that vaginal wall support is maintained by a delicate balance between the synthesis/assembly and degradation of elastic fibers in the vaginal wall. In this application, we propose to build on this solid foundation to (i understand the relative importance of elastic fiber structural integrity and protease activation in the pathogenesis of pelvic organ prolapse, (ii) investigate the contribution of a novel elastin microfibrillar protein, LTBP4, and TGF� signaling in the pathogenesis of pelvic organ prolapse, and (iii) utilize injectable nanoparticle hydrogels with or without estrogen to prevent or ameliorate development of vaginal prolapse after injury.