Targeting reactive aldehyde metabolism in endometriosis as a treatment strategy and a diagnostic biomarker

以子宫内膜异位症中的反应性醛代谢作为治疗策略和诊断生物标志物

• 批准号: 9572404
• 负责人: Stacy L McAllister
• 金额: $ 12.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9572404
• 关键词: Abdomen; Address; Affect; Aldehydes; Asians; Behavioral; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biology; Cells; Cyst; Data; Detection; Development; Development Plans; Diagnosis; Diagnostic; Disease; Disulfiram; Doctor of Philosophy; Endometrial; Endometrial Cyst; Endometrium; Environment; Enzyme Activators; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; Equipment; Experimental Models; Female of child bearing age; Follicular Fluid; Future; Gene Expression; Goals; Grant; Greater sac of peritoneum; Growth; Health; Human; Hyperalgesia; Knock-in; Knock-in Mouse; Measures; Mentors; Metabolism; Mission; Mitochondria; Modeling; Mus; National Institute of Child Health and Human Development; Nociception; Operative Surgical Procedures; Oxidative Stress; Pain; Pathogenesis; Peritoneal Fluid; Pharmaceutical Preparations; Phase; Production; Proestrus; Proteins; Rattus; Reproductive Process; Research; Research Personnel; Research Proposals; Research Training; Rodent; Role; Serum; Site; Stimulus; Techniques; Testing; Therapeutic; Time; Tissue Banks; Tissue Sample; Training; United States; Universities; Uterus; Vagina; Western Blotting; Wild Type Mouse; Woman; Women' s Health; Work; Writing; adduct; aldehyde dehydrogenases; career; career development; design; diagnostic biomarker; effective therapy; endometriosis; enzyme activity; experience; experimental study; genetic variant; improved; medical schools; novel; outcome forecast; pain relief; pain symptom; protein expression; research and development; response; screening; skills; standard care; targeted treatment; tool; treatment strategy

Project Summary Endometriosis is one of the few disorders in women's health research with little progress made in the last 20 years relative to screening, detection, prognosis, and treatment. Reactive aldehydes, formed during oxidative stress, are produced and elevated in women with endometriosis and are metabolized intracellularly by aldehyde dehydrogenase 2 (ALDH2). The central hypothesis of this K99/R00 proposal is that the balance of reactive aldehyde production and metabolism underlies endometriosis and endometriosis-associated pain. The research goal of this project is to determine the role of reactive aldehyde production and aldehyde metabolism in endometriosis to identify a novel treatment and biomarker for women suffering from endometriosis. This proposal includes a comprehensive research training and career development plan under the guidance of expert mentors, advisors, and contributors (Drs. Eric Gross, Daria Mochly-Rosen, Marcia Stefanick, Julie Christianson, and Linda Giudice). The Mentored Phase will be conducted at Stanford University School of Medicine, a world-class environment for training in cutting edge research and career development. During the K99 mentored training phase (Years 1-2): Aim 1 will determine if reactive aldehyde metabolism influences the development of endometriosis using ALDH2*2 knock-in mice with reduced aldehyde metabolism, an experimental model of endometriosis, and cutting-edge techniques to measure reactive aldehyde production and aldehyde metabolism. Aim 2 will determine if reactive aldehyde metabolism is altered in women with endometriosis using techniques from Aim 1 to analyze human endometrial tissue samples from women with and without endometriosis provided by the UCSF endometrial tissue bank. This phase will consist of training in biochemical techniques to measure reactive aldehyde production and metabolism, formal course work, mentoring, grant writing, and seminars to prepare Dr. Stacy McAllister for a career as an independent investigator in the women's health field with a particular focus on endometriosis. During the R00 independent research phase (Years 3-5): Aim 3 will determine if reactive aldehyde metabolism influences endometriosis-associated primary abdominal and secondary vaginal pain (hyperalgesia) using the skills mastered in the training phase, an endometriosis experimental model, unique equipment and specialized skills to assess hyperalgesia, and a novel ALDH2 activator (to increase reactive aldehyde metabolism). Overall, this research proposal addresses an important issue outlined by the NICHD mission statement that women suffer no harmful effects from the reproductive process. Further, this proposal will train a future leader in the endometriosis field to tackle the major health problem facing 1 in 10 women of childbearing age.

项目概要 子宫内膜异位症是女性健康研究中为数不多的疾病之一，在过去 20 年中进展甚微 与筛查、检测、预后和治疗相关的年数。氧化过程中形成的反应性醛 压力，在患有子宫内膜异位症的女性中产生并升高，并通过细胞内代谢 乙醛脱氢酶 2 (ALDH2)。该 K99/R00 提案的中心假设是，平衡 活性醛的产生和代谢是子宫内膜异位症和子宫内膜异位症相关疼痛的基础。这 该项目的研究目标是确定活性醛产生和醛代谢的作用 子宫内膜异位症，为患有子宫内膜异位症的女性确定一种新的治疗方法和生物标志物。 该提案包括在以下人员指导下的全面研究培训和职业发展计划： 专家导师、顾问和贡献者（Eric Gross 博士、Daria Mochly-Rosen、Marcia Stefanick、Julie 克里斯蒂安森和琳达朱迪斯）。指导阶段将在斯坦福大学学院进行 医学，为尖端研究和职业发展提供世界一流的培训环境。期间 K99 指导培训阶段（第 1-2 年）：目标 1 将确定活性醛代谢是否影响 使用醛代谢降低的 ALDH2*2 敲入小鼠开发子宫内膜异位症， 子宫内膜异位症实验模型和测量活性醛产生的尖端技术 和醛代谢。目标 2 将确定患有以下疾病的女性的活性醛代谢是否发生改变： 使用目标 1 中的技术分析患有子宫内膜异位症的女性的人类子宫内膜组织样本 且无子宫内膜异位症，由 UCSF 子宫内膜组织库提供。这一阶段将包括培训 测量活性醛产生和代谢的生化技术，正式课程作业， 指导、资助写作和研讨会，为史黛西·麦卡利斯特博士的独立职业生涯做好准备 女性健康领域的研究者，特别关注子宫内膜异位症。 在 R00 独立研究阶段（第 3-5 年）：目标 3 将确定反应性醛代谢是否 使用以下方法影响子宫内膜异位症相关的原发性腹部疼痛和继发性阴道疼痛（痛觉过敏） 培训阶段掌握的技能、子宫内膜异位症实验模型、独特的设备和专业知识 评估痛觉过敏的技能，以及一种新型 ALDH2 激活剂（以增加活性醛代谢）。 总体而言，本研究提案解决了 NICHD 使命宣言中概述的一个重要问题： 妇女不会受到生殖过程的有害影响。此外，该提案将培养未来的领导者 在子宫内膜异位症领域，解决十分之一的育龄妇女面临的主要健康问题。