Immunologic Contributions to the Endometriosis Phenotype

免疫学对子宫内膜异位症表型的影响

基本信息

批准号：
10604909
负责人：
Victoria Renee Stephens
金额：
$ 3.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604909
关键词：
Adoptive Transfer Adult Affect Animals Anti-Inflammatory Agents Area Benign Bone Marrow Cell physiology Cells Characteristics Chronic Communication Critical Thinking Data Data Analyses Development Diagnostic Dioxins Disease Dysmenorrhea Dyspareunia Endocrine Endocrine Disruptors Endocrine disruption Endometrial Endometrium Epigenetic Process Estradiol Etiology Exhibits Exposure to Fellowship Female Female Genital Diseases Formulation Fostering Functional disorder Generations Genes Genetic Predisposition to Disease Gland Goals Growth Gynecologic Human Immune Immunologic Surveillance Immunologics Immunophenotyping Immunotoxicology In Vitro Incidence Infection Infectious Agent Infertility Inflammation Inflammatory Inflammatory Response International Intervention Knowledge Laboratories Learning Life Link Macrophage Manuscripts Mediating Memory Metabolic Molecular Mucous Membrane Mus Onset of illness Pathogenesis Pathway interactions Peritoneal Phenotype Positioning Attribute Prevention strategy Process Progesterone Quality of life Reproductive Endocrinology Reproductive Immunology Research Research Personnel Resistance Retrograde Menstruation Role Scientist Site Stimulus System Technical Expertise Technology Tetrachlorodibenzodioxin Therapeutic Tissues Toxicant exposure Toxicology Training Uterine cavity Uterus Woman Work aged career combat debilitating pain disease phenotype endometriosis experience functional status human tissue improved in utero intraperitoneal member migration mouse model post-doctoral training prenatal exposure protein expression receptor expression reproductive reproductive tract response skills stem cells theories therapeutic target therapy development tool toxicant

项目摘要

PROJECT SUMMARY Endometriosis, the presence of endometrial tissue at an extra-uterine site, is a common yet enigmatic gynecologic disease that dampens the quality of life for approximately 10-15% of reproductive-aged women. Although endometriosis is regarded as a benign condition, many women with this disease experience chronic episodes of debilitating pain, dyspareunia, dysmenorrhea, and/or infertility. Numerous theories have attempted to explain disease pathogenesis including retrograde menstruation, a genetic predisposition, and altered differentiation of non-uterine cells. Unfortunately, theories to date have failed to explain all incidences of disease occurrence. Thus, I am exploring the possibility that endometriosis is an adult-onset disease that emerges due to an early life disruption of endocrine-immune cross-communication. I hypothesize that an in utero toxicant exposure trains bone marrow-derived immune progenitor cells (BMDCs) and subsequently promotes the development of endometriosis in adulthood. Immune cell training refers to the development of memory of a previous infection, but it is unknown whether immune cells similarly “remember” a past toxicant exposure. Nevertheless, our laboratory has shown that in utero TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure in mice results in a loss of uterine progesterone (P4) sensitivity and hyperinflammation as seen in women with endometriosis. Herein, I will utilize our established mouse model of toxicant exposure to determine if in utero TCDD exposure induces immune cell training prompting the development of the endometriosis-like uterine phenotype in adult mice. In Specific Aim 1, I will examine the relationship between toxicant-mediated peritoneal inflammation and reproductive dysfunction by characterizing the intraperitoneal immune phenotype and uterine phenotype of TCDD-exposed mice compared to wild-type C57/BL6 (WT) mice. Furthermore, I will determine if TCDD-mediated alterations of immune cells directly contribute to uterine dysfunction by adoptively transferring BMDCs from TCDD-exposed mice to control recipient mice. In Specific Aim 2, I will elucidate the molecular mechanisms underlying the TCDD-generated phenotype by examining the epigenetic, metabolic, and functional status of TCDD-exposed immune cells in comparison to unexposed immune cells. Overall, determining the specific contribution of immune cells to reduced P4 sensitivity within the uterus and identifying targetable pathways will determine the potential utility of immune cells as a diagnostic and/or therapeutic target. This proposal builds upon preliminary data that I have obtained and will provide me with the training I seek in reproductive toxicology, reproductive immunology, immunotoxicology, and immunometabolism. Aside from gaining this knowledge and technical skills, I will also gain necessary experience in data analysis, generation of manuscripts, communication of my results to scientific and lay audiences, and the formulation of testable hypotheses. At the conclusion of this fellowship, I will be well-positioned to undertake postdoctoral training in a leading laboratory and pursue my goal to be an independent investigator.

项目概要子宫内膜异位症，即子宫内膜组织存在于子宫外部位，是一种常见但神秘的疾病妇科疾病影响约 10-15% 育龄妇女的生活质量。尽管子宫内膜异位症被认为是一种良性病症，但许多患有这种疾病的女性会经历慢性子宫内膜异位症。已经尝试了多种理论来解释衰弱性疼痛、性交痛、痛经和/或不孕症的发作。解释疾病的发病机制，包括月经逆行、遗传倾向和不幸的是，迄今为止的理论未能解释所有疾病的发生。因此，我正在探索子宫内膜异位症是一种成人发病的疾病的可能性。内分泌免疫交叉通讯的早期生命中断，我勇敢地接受了子宫内的毒物。暴露会训练骨髓源性免疫祖细胞 (BMDC)，并随后促进成年期子宫内膜异位症的发展是指记忆力的发展。以前感染过，但尚不清楚免疫细胞是否同样“记住”过去的毒物暴露。尽管如此，我们的实验室表明，在子宫内接触 TCDD（2,3,7,8-四氯二苯并-对二恶英）小鼠会导致子宫孕酮 (P4) 敏感性丧失和过度炎症，正如患有在此，我将利用我们建立的毒物暴露小鼠模型来确定是否患有子宫内膜异位症。子宫内 TCDD 暴露诱导免疫细胞训练，促进子宫内膜异位症样子宫的发育在特定目标 1 中，我将研究毒物介导的腹膜之间的关系。通过表征腹膜内免疫表型和子宫来研究炎症和生殖功能障碍 TCDD 暴露小鼠与野生型 C57/BL6 (WT) 小鼠的表型此外，我将确定是否。 TCDD介导的免疫细胞改变通过过继性直接导致子宫功能障碍将 TCDD 暴露小鼠的 BMDC 转移到对照受体小鼠中。在具体目标 2 中，我将阐明这一点。通过检查表观遗传、代谢和代谢，了解 TCDD 产生表型的分子机制与未暴露的免疫细胞相比，暴露于 TCDD 的免疫细胞的功能状态。确定免疫细胞对子宫内 P4 敏感性降低的具体贡献，并确定可靶向途径将决定免疫细胞作为诊断和/或治疗的潜在效用该建议以我获得的初步数据为基础，将为我提供培训。寻求生殖毒理学、生殖免疫学、免疫毒理学和免疫代谢学。通过获得这些知识和技术技能，我还将获得必要的数据分析经验，手稿的生成，将我的成果传达给科学界和非专业观众，以及制定在本次研究金结束时，我将有能力从事博士后工作。在领先的实验室接受培训，并追求成为一名独立研究者的目标。