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: 10463237
• 负责人: Maria Stamou
• 金额: $ 7.25万
• 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/10463237
• 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; Hospitals; Hot flushes; Human; Human Genetics; Hypothalamic structure; Idiopathic Hypogonadotropic Hypogonadism; Incidence; Individual; Infertility; Inherited; Investigation; K-Series Research Career Programs; Lead; 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; Suggestion; Syndrome; 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; 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 尽管世界各地有6-12％的男性和男性患有不孕症，但完全的基因合奏 控制人类繁殖尚未完全表征。在这项研究中，PI将研究遗传 特发性性低肿瘤性低肿瘤（IHH）的背景，这是一种罕见的神经内分泌障碍 促性腺激素释放激素（GNRH）神经元信号的缺陷，导致青春期延迟和 不育。 60％的IHH患者的遗传病因尚不清楚。这种缺少的遗传力可以归因于 对于难以捉摸的遗传变异的表征不佳，例如拷贝数变异（CNV）很难 使用传统的测序技术（例如核型和微阵列）捕获。最近的优势 下一代测序允许从外显子组测序（ES）数据检测较小的CNV。在这个 研究，PI将在一大批IHH受试者（1,400）中使用此类尖端CNV调用算法 检查CNV对IHH缺失的遗传力的贡献，了解GNRH神经元生物学和 破译稀有和常见复制性疾病的遗传控制。 PI将探讨 已知和新颖的IHH基因的CNV，并将利用IHH患者和受试者的人类表型 招募到大规模的杨百翰生物库（将召集ES的CNV中的CNV）确定 CNV在人类疾病表达中的后果。 PI将完成拟议的工作 Seminara博士，Talkowski博士和Balasubramanian博士的遗产。 Seminara博士是Nichd-的PI 赞助P50国家繁殖与不育转化研究中心（NCTRI） - 中心 马萨诸塞州综合医院（MGH）的生殖医学（CRM），将提供所有可用的 资源（访问ES和表型数据库）成功地完成了他的研究建议 以及直接的心态，以促进她过渡到身体科学家的独立职业。博士 Talkowski是MGH基因组医学中心（CGM）的主任，并开创了新颖的CNV 方法。在他的指导下，PI将分析IHH，对照和生物库受试者中的ES ES CNV。博士 Talkowski还是基因组学核心的主任，该核心拥有所有资源的功能验证 将从PI的CNV分析（IPSC衍生的GNRH细胞）中出现的新型基因。最后，博士 Balasubramanian是NCTRI-CRM的助理主任，在研究人群方面有重要专家 用于人类遗传投资的生物库，并将为PI提供重要的指导 完成她的建议。此外，候选人将继续进行正式课程和定期参与 与生殖内分泌学和遗传学有关的研究会议。这个项目将有助于 发展临床研究和人类遗传学领域的技能，并代表一个全面的 计划确定CNV在罕见的遗传神经内分泌疾病中的作用，准备PI应用 获得职业发展奖，以继续她的培训成为独立的临床研究者。