Genetics of Male Infertility: A Marker of Overall Health

男性不育的遗传学：整体健康的标志

• 批准号: 10379346
• 负责人: Kyle Edwin Orwig
• 金额: $ 164.14万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379346
• 关键词: Adoption; Adult; Age; Benefits and Risks; Biological; CRISPR/Cas technology; Cardiovascular Diseases; Cell Maintenance; Center for Translational Science Activities; Child; Cities; Clinic; Communication; Complement; Counseling; Couples; Data; Data Coordinating Center; Development; Diagnosis; Disease; Education; Education and Outreach; Ensure; Epigenetic Process; Faculty Workshop; Family; Family member; Female; Fertility; Foundations; Genes; Genetic; Germ Cells; Health; High School Student; Human; Individual; Infertility; Institution; K-12 student; Knowledge; Lead; Learning Module; Life; Life Expectancy; Link; Male Infertility; Malignant Neoplasms; Medical; Medical center; Metabolic syndrome; Mission; Mutant Strains Mice; Mutation; New York; Oregon; Patient Recruitments; Patients; Phenotype; Pilot Projects; Policies; Pregnancy; Questionnaires; Recording of previous events; Reproduction; Reproductive Health; Reproductive Medicine; Research; Research Personnel; Science; Sertoli cell only syndrome; Somatic Cell; Specialized Center; Students; Sum; Technology; Testing; Testis; Time; Translating; Translations; United States; Universities; Variant; Washington; Well in self; Work; assisted reproduction; career; clinical development; clinical diagnostics; comorbidity; comorbidity Index; cost; data exchange; diagnostic screening; effectiveness evaluation; epidemiologic data; epigenome; female fertility; fertility preservation; gene therapy; genetic variant; genome editing; genome sequencing; human model; idiopathic infertility; improved; individualized medicine; junior high school; laboratory experiment; male; man; medical schools; men; mouse model; novel; personalized medicine; programs; prospective; reproductive; safety and feasibility; sertoli cell; stem cell function; stem cells; targeted treatment; teacher; underserved community; whole genome

Abstract: Overall Azoospermia impacts 1% of men globally, which translates to 645,000 men between the ages of 20 and 50 in the United States. It is estimated that genetic causes explain 50% of infertility. Epidemiological data suggest that fertility status may be a marker of overall health, but the genetic underpinnings are just beginning to be understood. Improved knowledge about the genetic basis of infertility and associated overall health comorbidities will aid in the counseling of infertile couples; justify the development of diagnostic screens; and may lead to patient-specific treatment options. In the current personalized medicine era with reduced cost whole genome sequencing and facile genome editing technologies, it is feasible to discover genetic underpinnings of infertility and overall health comorbidities and develop targeted therapies. Project I will discover genetic variants in men with azoospermia to identify targets for development of clinical diagnostics or therapy. Project I will use Charlson Comorbidity Index questionnaires to determine whether infertile patients or their family members have histories of other overall health comorbidities. Project II will validate infertility- associated genetic variants identified in Project I and characterize the fertility and overall health phenotypes. Project II will also work collaborate with Project III to determine the impact of epigenetic perturbations on spermatogonial stem cell function. Project III will develop Sertoli cell and germ cell gene therapies in mouse models of azoospermia and will produce critical safety and feasibility data to inform the public dialogue on the risks and benefits of gene therapy in and around the germline. The Pilot project will discover the epigenetic landscape of germ cells and somatic cells from the testes of fertile versus infertile men. Core A will provide the administrative oversight and facilitate communications and data exchange among projects and cores to ensure that this P50 program achieves an impact that is greater than the sum of its parts. The Education and Outreach Core will maximize the public impact of this P50 by developing hands-on teaching modules to educate middle school and high school students as well as adults in underserved communities about reproductive medicine and the genetics of infertility. Modules will be tested and validated in the Pitt Mobile Science lab before deploying to teacher workshops in St. Louis, Pittsburgh, Ithaca and New York allowing teachers to implement the modules in their classrooms. Male focused teaching modules will also be shared with P50 centers in Oregon and at Northwestern to complement their existing female-focused hands-on modules.

摘要：总体 Azoospermia影响了全球1％的男性，这转化为20至50岁的男性 美国。据估计，遗传原因解释了不育的50％。表明流行病学数据 生育状况可能是整体健康的标志，但遗传基础刚刚开始是 理解。改善了关于不育的遗传基础和相关整体健康的知识 合并症将有助于对不育夫妇的咨询；证明诊断的发展 屏幕；并可能导致特定于患者的治疗选择。在当前的个性化医学时代 降低成本整体基因组测序和便捷的基因组编辑技术，可行的发现是可行的 不孕症和整体健康合并症的遗传基础，并发展有针对性的疗法。项目i 将发现具有无植物体验的男性的遗传变异，以识别临床诊断发展的靶标 或治疗。项目我将使用Charlson合并症指数问卷来确定不育患者是否 否则他们的家人有其他整体健康合并症的历史。第二次项目将验证不育症 - 项目I中鉴定出的相关遗传变异，并表征了生育能力和整体健康表型。 项目II还将与III项目合作，以确定表观遗传扰动的影响 精子干细胞功能。 III项目将在小鼠中发展Sertoli细胞和生殖细胞基因疗法 Azoospermia的模型，并将产生关键的安全性和可行性数据，以告知公众对话 基因疗法在种系内及其周围的风险和益处。试点项目将发现表观遗传 生殖细胞和体细胞的景观来自肥沃的男性与不育男性的睾丸。核心A将提供 行政监督，并促进项目和核心之间的通信和数据交流，以确保 该P50计划的影响大于其部分的总和。教育和外展 核心将通过开发动手教学模块来教育中间的P50最大程度地影响该P50的公共影响 学校和高中生以及服务不足的社区中有关生殖医学的成年人 和不育的遗传学。模块将在皮特移动科学实验室进行测试和验证 部署在圣路易斯，匹兹堡，伊萨卡和纽约的教师研讨会上，允许教师实施 教室中的模块。以男性为中心的教学模块也将与P50中心共享 俄勒冈州和西北地区，以补充其现有的以女性为中心的动手模块。