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.

项目摘要子宫内膜异位症是子宫内膜组织在外部部位的存在，是一个常见但神秘的大约10-15％的复制年龄妇女的生活质量跳舞。尽管子宫内膜异位症被认为是一种良性疾病，但许多患有这种疾病的女性经历了慢性病衰弱的疼痛，全疾病，痛经和/或不育的发作。许多理论试图解释疾病发病机理，包括逆行月经，遗传易感性和改变非紫外线细胞的分化。不幸的是，迄今为止的理论未能解释所有疾病的发生率发生。那我正在探索子宫内膜异位症是一种成年疾病的可能性内分泌 - 免疫交叉通信的早期生命中断。我假设是子宫中的有毒物质暴露训练骨髓来源的免疫元素细胞（BMDC），随后促进成年子宫内膜异位症的发展。免疫细胞训练是指一A的记忆的发展先前的感染，但未知免疫球是否类似地“记住”了过去的毒性暴露。尽管如此，我们的实验室表明，在子宫内（2,3,7,8-四氯迪本培）中，小鼠导致子宫孕酮（P4）敏感性和高炎症的损失，如患有子宫内膜异位症。在此，我将利用我们已建立的毒物暴露的老鼠模型来确定是否在子宫TCDD暴露会诱导免疫球训练促使子宫内膜异位症的发展成年小鼠的表型。在特定目标1中，我将检查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的炎症和生殖功能障碍与野生型C57/BL6（WT）小鼠相比，暴露于TCDD的小鼠的表型。此外，我将确定是否 TCDD介导的免疫细胞的改变直接导致子宫功能障碍。从暴露于TCDD的小鼠中转移BMDC以控制受体小鼠。在特定目标2中，我将阐明通过检查表观遗传学，代谢和与意外的免疫球相比，暴露于TCDD暴露的免疫球的功能状态。全面的，确定免疫细胞对降低子宫内P4敏感性的特定贡献并确定可靶向途径将确定免疫细胞作为诊断和/或治疗的潜在效用目标。该建议建立在我获得的初步数据的基础上，并将为我提供培训I 寻求生殖毒理学，生殖免疫学，免疫毒理学和免疫代谢。旁边从获得这些知识和技术技能，我还将获得数据分析中必要的经验，稿件的产生，我的结果与科学和外行观众的交流以及公式可检验的假设。在这项奖学金结束时，我将有很好的位置进行博士后。在领先的实验室进行培训，并追求我的目标成为独立研究者。