SIRT1 as a Therapeutic Target in Endometriosis

项目2：SIRT 1作为子宫内膜异位症的治疗靶点 摘要 虽然，预后抵抗现在被认为是子宫内膜异位症病理生理学的关键因素， 其基本机制还不清楚。使用小鼠和非人类灵长类动物模型，以及 在人类组织中，我们已经开发了一种围绕组蛋白去乙酰化酶Sirtuin-1（SIRT 1）的假说， 其似乎在子宫内膜异位症的孕酮抵抗中起关键作用。引发 SIRT 1协调孕激素抵抗，似乎在炎症过程中具有病理生理作用。 在小鼠中与卵巢癌相关的不孕症。由于严重的慢性炎症引起的 在子宫内膜异位症中，SIRT 1在子宫内膜异位症女性的所有周期阶段都过表达。通过促进 孕激素抵抗，子宫内膜异位症变得自我维持和进行性， 促进雌激素的作用并减少孕激素的拮抗作用。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设 子宫内膜异位症模型。在项目2中，我们提出了协同研究，以补充这一目标 P01发展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 高度创新的工程小鼠模型，包括Sirt 1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报告物; 研究SIRT 1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， 将决定孕激素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，并确定了特定的转录组学和 表观遗传学的变化涉及孕激素抵抗和不育，依赖于SIRT 1过表达。 将在小鼠和人子宫内膜中比较这些孕酮抗性特征。在Aim中 2我们将进一步调查和探索非常真实的和令人兴奋的可能性，一个特定的SIRT 1抑制剂（EX-1）， 529; selisistat），在适当的剂量和时间给予，可以逆转孕酮抵抗和不孕症， 我们小鼠子宫内膜异位症模型中病变个体发生和进展。这些研究将有助于确定新的 机制目标，并为特定SIRT 1抑制剂的人体试验奠定基础， 为患有这种常见和毁灭性疾病的妇女提供更好的治疗选择。

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.