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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：
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
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/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

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