SIRT1 as a Therapeutic Target in Endometriosis

SIRT1 作为子宫内膜异位症的治疗靶点

基本信息

批准号：
10700024
负责人：
Jae-Wook Jeong
金额：
$ 42.47万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10700024
关键词：
Affect Age Bioinformatics Biological Availability 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 Lesion Maintenance Mediating Medical Menstrual cycle Modeling Molecular Mus Nature Operative Surgical Procedures Pelvic Pain Pharmaceutical Preparations Play Progesterone Progestins Recurrent disease Reporter Resistance Risk Role SIRT1 gene Signal Transduction Therapeutic Time Tissues Uterus Woman chronic pelvic pain endometriosis endometriosis-related infertility eutopic endometrium fertility preservation gene repression human tissue improved inhibitor 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

项目摘要

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点抽象的黄体酮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，尽管使用小鼠和非人类灵长类动物模型以及其基本机制尚不清楚。人类组织中，我们针对组蛋白脱乙酰酶 Sirtuin-1 (SIRT1) 提出了一个假设，这似乎在子宫内膜异位症引发的孕激素抵抗中发挥着关键作用。 SIRT1 协调黄体酮抵抗，这似乎在炎症过程中具有病理生理学作用由于严重的慢性炎症引起的小鼠子宫内膜异位症相关的不孕症。子宫内膜异位症患者中，SIRT1 在子宫内膜异位症女性的所有周期阶段均过度表达。孕激素抵抗，子宫内膜异位症变得自我维持和进展，伴随孕激素抵抗促进雌激素的作用并减少孕激素的拮抗作用。为临床前小鼠子宫内膜异位症的诊断和治疗提供独特的可测试假设在项目 2 中，我们提出了补充该项目总体目标的协同研究。 P01 开发子宫内膜异位症的诊断和治疗方法，我们将在两个具体目标中使用。创新的高度工程化小鼠模型，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产生器；研究 SIRT1 在子宫内膜异位症孕激素抵抗中的作用以及临床前评估；在目标 1 中，我们使用 FDA 批准的亨廷顿病药物来治疗子宫内膜异位症。将确定孕激素抵抗和子宫内膜异位症进展的本质。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黄体酮抵抗和不孕症相关的表观遗传变化取决于 SIRT1 的过度表达。 In Aim 将在小鼠和人类子宫内膜中比较这些黄体酮抗性特征。 2 我们将进一步研究和探索特定 SIRT1 抑制剂（EX- 529；selisisat），以适当的剂量和时间给予，可以逆转黄体酮抵抗和不孕症并治疗这些研究将有助于确定新的小鼠子宫内膜异位症模型中的病变个体发生和进展。机制目标并为特定 SIRT1 抑制剂的人体试验奠定基础，该抑制剂可以显着改善患有这种常见且毁灭性疾病的女性的治疗选择。