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

项目摘要 子宫内膜异位症是女性健康研究中为数不多的几种疾病之一，在过去的20年里进展甚微 与筛查、检测、预后和治疗相关的年份。氧化过程中形成的反应性醛 应激在子宫内膜异位症患者体内产生和升高，并通过细胞内代谢 乙醛脱氢酶2(ALDH2)。这个K99/R00方案的中心假设是 反应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。这个 本项目的研究目标是确定反应醛的产生和醛的代谢的作用。 旨在为子宫内膜异位症患者寻找一种新的治疗方法和生物标志物。 该提案包括一项全面的研究、培训和职业发展计划，该计划由 专家导师、顾问和贡献者(Eric Gross博士、Daria Mochly-Rosen博士、Marcia Stefan ick博士和Julie博士 克里斯汀森和琳达·朱迪斯)。指导阶段将在斯坦福大学学院进行 医学，一个世界级的尖端研究和职业发展培训环境。在.期间 K99指导训练阶段(1-2年)：目标1将确定反应醛代谢是否影响 用醛代谢降低的ALDH2*2敲入小鼠发展子宫内膜异位症 子宫内膜异位症的实验模型和测量反应醛产生的尖端技术 和乙醛代谢。Aim 2将确定女性的反应性醛代谢是否发生改变 使用Aim 1的技术分析患有子宫内膜异位症的妇女的子宫内膜组织样本 并且没有由加州大学旧金山分校子宫内膜组织库提供的子宫内膜异位症。这一阶段将包括以下培训 测量反应醛产生和代谢的生物化学技术，正规课程作业， 指导、赠款写作和研讨会，为Stacy McAllister博士的独立职业生涯做好准备 妇女健康领域的调查员，特别关注子宫内膜异位症。 在R00独立研究阶段(3-5年)：目标3将确定反应醛代谢 影响子宫内膜异位症相关的原发性腹痛和继发性阴道疼痛(痛觉过敏) 在培训阶段掌握的技能，子宫内膜异位症实验模型，独特的设备和专门的 评估痛觉过敏的技能，以及一种新的ALDH2激活剂(增加反应醛代谢)。 总体而言，这项研究提案解决了NICHD任务说明中概述的一个重要问题 女性在生殖过程中不会受到有害影响。此外，这项提议将培养一位未来的领导人 在子宫内膜异位症领域，解决每10名育龄妇女中就有1人面临的主要健康问题。

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.