The Massachusetts General Hospital Harvard Center for Reproductive Medicine

项目摘要 不孕症影响了地球仪上多达13%的育龄夫妇，但不孕症的潜在机制基础是， 不孕症和不孕症作为一般健康的总体标志的作用尚不清楚。这些知识差距阻碍了 诊断、治疗和预防不孕导致的身体、心理和经济负担， 不孕不育的夫妇为了应对这些挑战，马萨诸塞州总医院哈佛中心 生殖医学已经组建了一个由具有生殖医学专业知识的研究人员组成的综合团队。 医学，基因组学，群体遗传学和遗传素养，他们将进行临床转化研究 目的1：通过透镜阐明不孕症的遗传和表型结构 目标2：促进建立一个合作智囊团，重点是减少 不孕症的痛苦和代价，以一种外向的方式，前瞻性的思维和整合全球 目标3：成为一个充满活力的外联、培训和社区参与中心， 科学团队更接近他们所服务的患者，他们想要指导的学员，以及更大的社区， 科学家和临床医生致力于减轻不孕症造成的负担。这些目标将是 通过两个临床研究项目实现，该项目将得到基因组学和功能核心的支持， 外展核心和行政核心。项目1将进行下一代测序， 临床队列中基因型驱动的表型研究，丰富了混合遗传驱动的不孕症 和具有低促性腺激素和高促性腺激素特征的近亲群体 两性性腺功能减退症。项目2将汇集超过180万个多族裔人口生物库样本 进行全基因组关联研究、全表型关联研究和孟德尔随机化 研究涉及决定生育力的关键生物途径，并综合不孕症的遗传结果 和相关性状，以表征所确定的基因和途径对生殖健康的影响， 总体发病率。基因组学和功能核心将提供基因组技术，数据分析， 计算和统计支持，并将产生基因工程人类诱导多能细胞 用于验证项目1和2的基因发现。外联核心将通过以下方式支持项目1和2的活动： 通过患者小组会议吸引关键利益相关者，创建面向临床医生的材料， 交流遗传结果，并推出一个受设计思维启发的网站，以广泛传播， 患者、家属和临床医生。行政核心将通过提供以下服务来推进中心的科学目标： 及时提供支持，以促进研究者、患者、研究学员之间的参与和沟通， 更广泛的学术界。通过这些相互交织的活动，该中心将培训下一个 生殖生物学家的产生及其活动产生的结果将有助于告知临床护理 减轻不孕症患者的痛苦。

PROJECT ABSTRACT Infertility affects up to 13% of reproductive age couples across the globe but the underlying mechanistic basis of infertility and the role of infertility as an overall marker of general health is unclear. These knowledge gaps hinder the diagnosis, treatment and prevention of infertility leading to physical, psychological and financial burden to couples with infertility. To address these challenges, The Massachusetts General Hospital Harvard Center for Reproductive Medicine has assembled an integrative team of investigators with expertise in reproductive medicine, genomics, population genetics and genetic literacy who will conduct clinical translational investigation in humans with infertility: Aim 1: To elucidate the genetic and phenomic architecture of infertility through the lens of specific rare diseases and common traits; Aim 2: To catalyze a collaborative think-tank focused on reducing the suffering and costs of infertility, in a manner that is outward looking, forward thinking and integrates global perspectives; Aim 3: To nucleate a vibrant hub for outreach, training and community engagement that brings the scientific team closer to the patients they serve, the trainees they want to mentor, and the larger community of scientists and clinicians who are invested in reducing the burdens caused by infertility. These aims will be achieved using two Clinical Research projects which will be supported by a Genomics and Functional Core, Outreach Core and Administrative Core. Project 1 will perform next-generation sequencing and targeted genotype-driven phenotyping studies in clinical cohorts enriched for genetically driven infertility from admixed and consanguineous populations characterized by both hypogonadotropic and hypergonadotropic hypogonadism in both sexes. Project 2 will bring together >1,800,000 multi-ethnic population biobank samples to perform genome-wide association studies, phenome-wide association studies, and Mendelian randomization studies to implicate key biologic pathways determining fertility and synthesize the genetic results across infertility and related traits to characterize the effects of the identified genes and pathways on reproductive health and overall morbidity. The Genomics and Functional Core will provide genomic technologies, data analytics, computational and statistical support, and will generate genetically engineered human induced pluripotent cells for validation of Project 1 & 2 genetic discoveries. The Outreach Core will buoy Project 1 & 2 activities by engaging key stakeholders through patient group meetings, creating clinician-facing materials to enable communication of genetic results and launch a website inspired by design-thinking for broad dissemination to patients, families and clinicians. The Administrative Core will advance the Center’s scientific goals by providing timely support to foster engagement and communication between investigators, patients, research trainees and the broader academic community. Through these interdigitating activities, the Center will train the next generation of reproductive biologists and the results emanating from its activities will help inform clinical care and alleviate the suffering of patients with infertility.