Deciphering the Role of Copy Number Variants in Neuroendocrine Disorders of Infertility

解读拷贝数变异在不孕症神经内分泌疾病中的作用

• 批准号: 10663071
• 负责人: Maria Stamou
• 金额: $ 7.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663071
• 关键词: Age; Algorithms; Amenorrhea; Architecture; Area; Award; Base Pairing; Biological Factors; Biology; Cardiovascular system; Cells; Center for Translational Science Activities; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical Investigator; Code; Complex; Copy Number Polymorphism; Data; Databases; Defect; Delayed Puberty; Detection; Diabetes Mellitus; Diagnostic; Disease; Enrollment; Environment; Exhibits; Fellowship; Fertility; General Hospitals; Genes; Genetic; Genetic Materials; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genomic DNA; Genomic medicine; Genomics; Genotype; Goals; Gonadotropin Hormone Releasing Hormone; Grant; Health; Hereditary Disease; Heritability; Heterozygote; Hospitals; Hot flushes; Human; Human Genetics; Hypothalamic structure; Idiopathic Hypogonadotropic Hypogonadism; Incidence; Individual; Infertility; Inherited; Investigation; K-Series Research Career Programs; Link; Malignant - descriptor; Massachusetts; Mendelian disorder; Menopause; Mentors; Mentorship; Molecular; Names; National Institute of Child Health and Human Development; Neurons; Neuropeptides; Neurosecretory Systems; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Polycystic Ovary Syndrome; Population; Population Genetics; Precocious Puberty; Predisposition; Prevalence; Proteins; Reproduction; Reproductive Biology; Reproductive Endocrinology; Reproductive Medicine; Research; Research Personnel; Research Proposals; Resources; Role; Scientist; Single Nucleotide Polymorphism; Technology; Training; Untranslated RNA; Validation; Variant; Woman; Work; biobank; career; clinical investigation; cohort; defined contribution; exome sequencing; gene discovery; genetic architecture; genetic variant; human disease; improved; induced pluripotent stem cell; insight; meetings; men; neurotransmission; new therapeutic target; next generation sequencing; novel; phenome; phenomics; rare genetic disorder; rare mendelian disorder; reproductive; reproductive system disorder; skill acquisition; study population; tool; translational impact

PROJECT ABSTRACT Despite 6-12% of women and men around the world suffering from infertility, the full ensemble of genes that control human reproduction has not been fully characterized. In this study, the PI will study the genetic background of Idiopathic Hypogonadotropic Hypogonadism (IHH), a rare neuroendocrine disorder caused by defects in Gonadotropin Releasing Hormone (GnRH) neuronal signaling, that leads to delayed puberty and infertility. The genetic etiology in 60% of IHH patients remains unknown. This missing heritability can be attributed to poor characterization of elusive genetic variation such as copy number variants (CNVs) that are hard to capture using traditional sequencing technologies, such as karyotypes and microarrays. Recent advantages in next generation sequencing have allowed detection of smaller CNVs from exome sequencing (ES) data. In this study, the PI will utilize such cutting edge CNV calling algorithms in a large cohort of IHH subjects (1,400) to examine the contribution of CNVs to the missing heritability of IHH, understand the GnRH neuronal biology and decipher the genetic control of rare and common reproductive disorders. The PI will explore the contribution of CNVs to known and novel IHH genes and will utilize human phenotypes from the IHH patients and subjects enrolled to the Mass General Brigham biobank (in whom CNVs from ES will be called) to determine the consequences of CNVs in human disease expression. The PI will complete the proposed work under the mentorship of Dr. Seminara, Dr. Talkowski and Dr. Balasubramanian. Dr. Seminara is the PI of a NICHD- sponsored P50 National Center of Translational Research in Reproduction and Infertility (NCTRI) – Center for Reproductive Medicine (CRM) at the Massachusetts General Hospital (MGH) and will provide all available resources (access to ES and phenotypic databases) for the successful completion of his research proposal as well as direct mentorship to facilitate her transition to an independent career as a physician scientist. Dr. Talkowski is the Director for the Center of Genomic Medicine (CGM) at MGH and has pioneered novel CNV approaches. Under his guidance, the PI will analyze ES derived CNVs in IHH, control and biobank subjects. Dr. Talkowski is also the Director of the Genomics Core that houses all the resources for the functional validation of the novel genes that will emerge from the PI’s CNV analyses (IPSc derived GnRH cells). Finally, Dr. Balasubramanian is the Assistant Director of the NCTRI-CRM with significant expertise in studying population biobanks for human genetic investigations and will provide important guidance to the PI for the successful completion of her proposal. In addition, the candidate will pursue formal coursework and regular engagement in research meetings related to both reproductive endocrinology and genetics. This project will facilitate development of skills in the areas of clinical investigation and human genetics and represents a comprehensive plan to identify the role of CNVs in rare inherited neuroendocrine disorders of infertility, preparing the PI to apply for a career development award to continue her training to become an independent clinical investigator.

项目摘要 尽管全世界有 6-12% 的女性和男性患有不孕症，但基因组 人类生殖的控制尚未得到充分表征。在本研究中，PI 将研究遗传 特发性低促性腺激素性性腺功能减退症（IHH）的背景，这是一种罕见的神经内分泌疾病，由 促性腺激素释放激素 (GnRH) 神经元信号传导缺陷，导致青春期延迟和 不孕症。 60% IHH 患者的遗传病因仍不清楚。这种缺失的遗传力可以归因于 对难以捉摸的遗传变异的不良表征，例如难以识别的拷贝数变异（CNV） 使用传统测序技术（例如核型和微阵列）进行捕获。近期优势 新一代测序可以从外显子组测序 (ES) 数据中检测更小的 CNV。在这个 研究中，PI 将在一大群 IHH 受试者 (1,400) 中使用这种尖端的 CNV 调用算法，以 检查 CNV 对 IHH 遗传性缺失的贡献，了解 GnRH 神经元生物学并 破译罕见和常见生殖疾病的遗传控制。 PI 将探索以下贡献： 已知和新型 IHH 基因的 CNV，并将利用 IHH 患者和受试者的人类表型 登记到麻省总医院布里格姆生物库（其中将调用来自 ES 的 CNV）以确定 CNV 在人类疾病表达中的影响。 PI 将完成拟议的工作 Seminara 博士、Talkowski 博士和 Balasubramanian 博士的指导。 Seminara 博士是 NICHD 的 PI- 赞助 P50 国家生殖与不孕症转化研究中心 (NCTRI) – 中心 马萨诸塞州总医院 (MGH) 的生殖医学 (CRM) 部门将提供所有可用的 成功完成他的研究计划的资源（访问 ES 和表型数据库） 以及直接指导，以促进她过渡到作为一名医师科学家的独立职业。博士。 Talkowski 是麻省总医院基因组医学中心 (CGM) 主任，开创了新型 CNV 接近。在他的指导下，PI 将分析 IHH、对照和生物样本库受试者中 ES 衍生的 CNV。博士。 Talkowski 也是基因组学核心的主任，该核心拥有用于功能验证的所有资源 PI 的 CNV 分析（IPSc 衍生的 GnRH 细胞）中将出现的新基因。最后，博士。 Balasubramanian 是 NCTRI-CRM 的助理主任，在人口研究方面拥有丰富的专业知识 人类基因研究生物样本库，将为 PI 的成功研究提供重要指导 完成她的提议。此外，候选人将继续学习正式课程并定期参与 与生殖内分泌学和遗传学相关的研究会议。该项目将促进 临床研究和人类遗传学领域技能的发展，代表了全面的 计划确定 CNV 在罕见的遗传性神经内分泌不孕症中的作用，准备 PI 的应用 获得职业发展奖，以继续接受培训，成为一名独立的临床研究者。