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 全球多达13%的育龄夫妇会受到不孕不育的影响，但不孕不育的潜在机制基础 不孕不育和不孕不育作为总体健康标志的作用尚不清楚。这些知识差距阻碍了 诊断、治疗和预防导致身体、心理和经济负担的不孕不育 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具有生殖专业知识的综合研究团队 医学、基因组学、人口遗传学和遗传素养谁将进行临床翻译研究 在患有不孕症的人类中：目标1：通过晶状体阐明不孕症的遗传和表型结构 关于特定的罕见疾病和共同特征；目标2：推动建立一个合作智囊团，侧重于减少 不孕不育的痛苦和代价，以一种向外看的、前瞻性的思维和全球一体化的方式 观点；目标3：为外联、培训和社区参与提供一个充满活力的枢纽，从而带来 科学团队更贴近他们服务的患者、他们想要指导的受训人员以及更大的社区 致力于减轻不孕不育负担的科学家和临床医生。这些目标将是 通过两个临床研究项目实现，这两个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将执行下一代测序并有针对性 混合型遗传性不孕症患者临床队列中的基因驱动表型研究 和具有低促性腺激素和高促性腺激素特征的近亲种群 性腺功能减退症在两性中都存在。项目2将汇集180万份多民族人口生物库样本 进行全基因组关联研究、全表型关联研究和孟德尔随机化 涉及决定生育能力的关键生物途径和综合不育的遗传结果的研究 和相关性状，以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，并将产生基因工程的人类诱导多能细胞 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和项目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以实现 传播遗传结果，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。管理核心将通过提供以下内容来推进中心的科学目标 及时提供支持，促进研究人员、患者、研究实习生和 更广泛的学术界。通过这些交错活动，该中心将培训下一位 生殖生物学家的产生及其活动产生的结果将有助于临床护理 减轻不孕症患者的痛苦。