Targeting Reactive Aldehyde Metabolism in Endometriosis as a treatment strategy and a Diagnostic Biomarker

项目摘要 子宫内膜异位症是妇女健康研究中为数不多的疾病之一，在过去的20年里几乎没有取得进展。 年相对于筛查，检测，预后和治疗。反应性醛，在氧化过程中形成 子宫内膜异位症妇女产生和升高， 醛脱氢酶2（ALDH 2）。K99/R 00提案的核心假设是， 反应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。的 本项目的研究目标是确定反应性醛产生和醛代谢的作用 在子宫内膜异位症，以确定一种新的治疗和生物标志物的妇女患有子宫内膜异位症。 该提案包括在以下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、Daria Mochly-Rosen、Marcia Stefanick、Julie Christianson和琳达朱迪斯）。指导阶段将在斯坦福大学学院进行， 医学，一个世界一流的环境，在尖端研究和职业发展的培训。期间 K99指导培训阶段（1-2年级）：目标1将确定反应性醛代谢是否影响 使用醛代谢降低的ALDH 2 *2基因敲入小鼠， 子宫内膜异位症的实验模型，以及测量反应性醛产生的尖端技术 和醛代谢。目的2将确定是否反应性醛代谢改变妇女与 使用Aim 1的技术分析来自患有子宫内膜异位症的女性的人类子宫内膜组织样本， 并且没有UCSF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： 生物化学技术来测量反应性醛的生产和代谢，正式的课程工作， 指导，赠款写作和研讨会，以准备博士斯泰西麦卡利斯特作为一个独立的职业生涯 女性健康领域的调查员，特别关注子宫内膜异位症。 在R 00独立研究阶段（第3-5年）：目标3将确定反应性醛代谢是否 影响子宫内膜异位症相关的原发性腹部和继发性阴道疼痛（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，独特的设备和专业 评估痛觉过敏的技能和一种新的ALDH 2激活剂（以增加反应性醛代谢）。 总的来说，这项研究提案解决了NICHD使命声明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，这一建议将培养未来的领导者 在子宫内膜异位症领域，解决十分之一育龄妇女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.