SIRT1 as a Therapeutic Target in Endometriosis

项目2：SIRT1作为子宫内膜异位症的治疗靶点 摘要 黄体酮抵抗现在被认为是子宫内膜异位症病理生理过程中的一个关键因素 其潜在的机制还没有被很好地理解。使用老鼠和非人灵长类动物模型，以及 我们围绕组蛋白去乙酰化酶Sirtuin-1(SIRT1)提出了一个假说， 这似乎在子宫内膜异位症的孕激素抵抗中起着关键作用。触发者 炎症，SIRT1协调孕酮抵抗，似乎在 小鼠子宫内膜异位症相关不孕症。由于引起的严重和慢性炎症 子宫内膜异位症，SIRT1在子宫内膜异位症患者的所有周期阶段都有过表达。通过推广 黄体酮抵抗，子宫内膜异位症会自我维持和进展，并伴有黄体酮抵抗 促进雌激素作用，抑制孕激素的拮抗作用。理解这些原则 为临床前小鼠子宫内膜异位症的诊断和治疗提供了独特的可检验假说 子宫内膜异位症模型。在项目2中，我们提出了协同研究，以补充这一覆盖目标 P01开发子宫内膜异位症的诊断和治疗方法。在两个具体目标中，我们将使用 高度创新的转基因小鼠模型，包括Sirt1过表达和子宫内膜异位症模型 用于非侵入性成像的生物发光和荧光记者.综合生物信息学分析 探讨SIRT1在子宫内膜异位症孕酮抵抗中的作用； 使用FDA批准的亨廷顿病药物治疗子宫内膜异位症的新方法。在目标1中，我们 将决定黄体酮抵抗和子宫内膜异位症进展的本质。我们将研究 子宫内膜异位症的结构、分子和炎症特征，并确定特定的转录和 表观遗传学改变涉及孕激素抵抗和依赖于SIRT1过度表达的不孕不育。 这些黄体酮抵抗信号将在小鼠和人类子宫内膜中进行比较。在AIM 2我们将进一步调查和探索一种非常真实和令人兴奋的可能性，即一种特定的SIRT1抑制剂(前- 在适当的剂量和时间给药，可以逆转黄体酮抵抗和不孕症，并治疗 我们的小鼠子宫内膜异位症模型中的病变个体发生和进展。这些研究将有助于确定新的 机制靶点并为特定SIRT1抑制剂的人体试验奠定了基础，这可能会极大地 改善患有这种常见和毁灭性疾病的女性的治疗选择。

Project 2: SIRT1 as a Therapeutic Target in Endometriosis ABSTRACT Progesterone resistance is now recognized as a key element in the pathophysiology of endometriosis, though its underlying mechanism is not well understood. Using mouse and non-human primate models, as well as human tissues, we have developed a hypothesis surrounding the histone deacetylase Sirtuin-1 (SIRT1), which appears to play a critical role in progesterone resistance of endometriosis. Triggered by inflammation, SIRT1 orchestrates progesterone resistance that appears to have a pathophysiological role during endometriosis-related infertility in the mouse. Due to profound and chronic inflammation elicited by endometriosis, SIRT1 is overexpressed during all cycle stages in women with endometriosis. By promoting progesterone resistance, endometriosis becomes self-sustaining and progressive, with progesterone resistance promoting estrogen action and curtailing the antagonistic effects of progestins. Understanding these principles provides unique testable hypotheses for both the diagnosis and treatment of endometriosis in a preclinical mouse model of endometriosis. In Project 2, we propose synergistic studies that complement the overlying goal of this P01 to develop both diagnostic and therapeutic approaches to endometriosis. In two specific aims we will use highly innovative engineered mouse models, including Sirt1 overexpression and endometriosis models with bioluminescent and fluorescent reporters for non-invasive imaging; integrated bioinformatic analysis to investigate the role of SIRT1 in the progesterone resistance of endometriosis; and preclinical assessment of a new therapeutic approach for endometriosis using an FDA-approved drug for Huntington’s disease. In Aim 1 we will determine the essential nature of progesterone resistance and endometriosis progression. We will examine structural, molecular, and inflammatory features of endometriosis and define the specific transcriptomic and epigenetic changes involved in progesterone resistance and infertility that depend on SIRT1 overexpression. These progesterone resistance signatures will be compared in both the mouse and human endometrium. In Aim 2 we will further investigate and explore the very real and exciting possibility that a specific SIRT1 inhibitor (EX- 529; selisistat), given at the proper dose and time, can reverse progesterone resistance and infertility and treat lesion ontogeny and progression in our mouse endometriosis model. These studies will serve to identify new mechanistic targets and set the stage for human trials of specific SIRT1 inhibitors that could dramatically improve therapeutic options for women with this common and devastating disease.