The Massachusetts General Hospital Harvard Center for Reproductive Medicine

马萨诸塞州总医院哈佛生殖医学中心

• 批准号: 10463543
• 负责人: Stephanie Beth Seminara
• 金额: $ 155.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463543
• 关键词: Address; Affect; Age; Architecture; Biological; Biological Factors; Biological Process; Boston; Brain; Cells; Center for Translational Science Activities; Child; Clinical; Clinical Research; Clinical Treatment; Collection; Communication; Communities; Computational Biology; Counseling; Couples; Creativeness; DNA; Data Analytics; Denmark; Diagnosis; Disease; Education and Outreach; Endocrinology; Estonia; Ethnic group; Faculty; Family; Fertility; Financial Hardship; Finland; Fostering; Future; GNRH1 gene; General Hospitals; Genes; Genetic; Genetic Engineering; Genomics; Genotype; Goals; Gonadal structure; Group Meetings; Gynecology; Health; Hospitals; Human; Human Development; Human Engineering; Hypogonadism; Individual; Infertility; Information Dissemination; Institution; Interdisciplinary Study; International; Investigation; Knowledge; Lead; Leadership; Link; Longitudinal Studies; Massachusetts; Mendelian randomization; Mentors; Mentorship; Methodology; Methods; Morbidity - disease rate; Mutation; National Institute of Child Health and Human Development; Parents; Pathway interactions; Patients; Pediatric Surgical Procedures; Penetrance; Phenotype; Physiological; Population; Population Genetics; Positioning Attribute; Prevention; Provider; Public Health; Rare Diseases; Reproduction; Reproductive Biology; Reproductive Health; Reproductive Medicine; Research; Research Personnel; Research Project Grants; Resources; Role; Sampling; Scientist; Services; Strategic vision; Technology; Therapeutic; Thinking; Time; Training; Urology; Validation; Work; biobank; clinical care; clinical investigation; cohort; community engagement; computerized tools; cost; design; evidence base; flexibility; functional genomics; gene discovery; gene function; genetic architecture; genome editing; genome wide association study; genomic variation; gonad development; human disease; improved; infertility treatment; innovation; lens; literacy; member; mortality; multi-ethnic; neuron development; next generation; next generation sequencing; outreach; phenome; phenomics; population based; psychologic; reproductive; research and development; sex; skills; sustainable resource; targeted treatment; trait; transcriptomics; translational scientist; web site

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.

项目摘要 不孕不育影响着全球高达 13% 的育龄夫妇，但其潜在的机制基础 不孕症以及不孕症作为总体健康总体指标的作用尚不清楚。这些知识差距阻碍了 不孕症的诊断、治疗和预防给患者带来身体、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 生殖医学组建了一支由具有生殖专业知识的综合研究人员组成的团队 医学、基因组学、群体遗传学和遗传素养将进行临床转化研究 在人类不孕症中：目标 1：通过透镜阐明不孕症的遗传和表型结构 具体的罕见疾病和共同特征；目标 2：促进建立一个专注于减少 以外向型、前瞻性思维和整合全球的方式，解决不孕不育带来的痛苦和代价 观点；目标 3：建立一个充满活力的外展、培训和社区参与中心，使 科学团队更接近他们所服务的患者、他们想要指导的受训者以及更大的社区 致力于减轻不孕不育造成的负担的科学家和临床医生。这些目标将是 使用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将进行下一代测序和靶向 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 以及具有低促性腺激素和高促性腺激素特征的近亲人群 两性性腺功能减退症。项目 2 将汇集超过 1,800,000 个多种族人口生物样本库样本 进行全基因组关联研究、全表型关联研究和孟德尔随机化 研究揭示决定生育能力的关键生物学途径并综合不孕症的遗传结果 和相关特征来表征已识别的基因和途径对生殖健康和 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。外展核心将通过以下方式支持项目 1 和 2 活动： 通过患者小组会议吸引主要利益相关者，创建面向临床医生的材料，以实现 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： 及时支持，促进研究者、患者、研究实习生和研究人员之间的参与和沟通 更广泛的学术界。通过这些相互交叉的活动，中心将培训下一代 生殖生物学家的产生及其活动产生的结果将有助于为临床护理提供信息 并减轻不孕不育患者的痛苦。