SIRT1 as a Therapeutic Target in Endometriosis

SIRT1 作为子宫内膜异位症的治疗靶点

• 批准号: 10309093
• 负责人: Jae-Wook Jeong
• 金额: $ 38.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10309093
• 关键词: Affect; Age; Bioavailable; Bioinformatics; Chronic; Complement; Development; Diagnosis; Diagnostic; Disease; Disease regression; Dose; Elements; Endometrial; Endometrium; Engineering; Epigenetic Process; Estrogens; Event; FDA approved; Functional disorder; Genes; Goals; Growth; HDAC4 gene; Histone Deacetylase; Human; Huntington Disease; Impairment; Incidence; Infertility; Inflammation; Inflammatory; Lead; Lesion; Maintenance; Mediating; Medical; Menstrual cycle; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Pelvic Pain; Pharmaceutical Preparations; Play; Progesterone; Progestins; Recurrence; Reporter; Resistance; Risk; Role; SIRT1 gene; Signal Transduction; Structure; Therapeutic; Time; Tissues; Uterus; Woman; base; chronic pelvic pain; endometriosis; endometriosis-related infertility; eutopic endometrium; fertility preservation; gene repression; human tissue; improved; inhibitor/antagonist; innovation; mouse model; non-invasive imaging; nonhuman primate; novel; novel strategies; novel therapeutic intervention; overexpression; pre-clinical; pre-clinical assessment; reproductive; response; side effect; therapeutic target; transcriptomics

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.

项目2：SIRT1作为子宫内膜异位症的治疗靶标 抽象的 现在，孕酮的耐药性被认为是子宫内膜异位症病理生理学中的关键元素。 使用小鼠和非人类的灵长类动物模型，其基本机制尚未得到充分理解 人体组织，我们围绕组蛋白脱氨酶Sirtuin-1（SIRT1）的假设， 触发的似乎在子宫内膜异位症的孕激素抵抗中起着至关重要的作用。 炎症，SIRT1在孕酮中策划了孕酮，以在 小鼠中与子宫内膜异位症相关的不育症。 子宫内膜异位症，在子宫内膜异位症的女性中，SIRT1过表达 孕激素耐药性，子宫内膜异位症成为自我维持和进行性，孕酮耐药性 促进雌激素作用并减少孕激素的拮抗作用。 为临床前小鼠诊断和治疗子宫内膜异位症提供了独特的可测试假设 子宫内膜异位症的模型。 P01在两个特定目标中都开发了子宫内膜异位症的诊断和治疗方法。 高度创新工程的小鼠模型，将SIRT1的过表达和子宫内膜异位症模型与 用于非侵入成像的生物发光和荧光记者； 研究SIRT1在子宫内膜异位症的孕酮耐药性中的作用； 使用FDA批准的亨廷顿氏病的新型子宫内膜异位症。 我们将研究孕酮的基本性质和子宫内膜异位症的进展 子宫内膜异位症的结构，分子和炎症特征，并定义特定的转录组和 孕激素抵抗和不育的表观遗传变化取决于SIRT1的过表达。 在AIM中，将比较这些孕酮的标志。 2我们将进一步调查并探索特定的SIRT1抑制剂（Ex- 529; Selistat以适当的剂量和时间给予 我们的小鼠子宫内膜异位症模型中的个体发育和进展。 机械靶标，并为特定SIRT1抑制剂的人体试验奠定了基础 通过这种常见和贬低的疾病改善治疗选择。