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: 10005443
• 负责人: Kyle Edwin Orwig
• 金额: $ 167.62万
• 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/10005443
• 关键词: Adoption; Adult; Age; Benefits and Risks; Biological; CRISPR/Cas technology; Cardiovascular Diseases; Cell Maintenance; Cell physiology; Center for Translational Science Activities; Child; Cities; Clinic; Communication; Communities; 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 cells; targeted treatment; teacher; 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 无精子症影响全球1%的男性，这相当于64.5万名20岁至50岁的男性 美国。据估计，50%的不孕症是由遗传因素造成的。流行病学数据表明 生育状况可能是整体健康的标志，但基因基础才刚刚开始 明白了。提高对不孕不育的遗传基础和相关整体健康的认识 合并症将有助于不育夫妇的咨询；证明诊断的发展是合理的 筛查；并可能导致针对患者的治疗选择。在当前的个性化医疗时代， 降低成本的全基因组测序和便捷的基因组编辑技术，可以发现 不孕不育的遗传基础和总体健康并存，并开发有针对性的治疗方法。项目一 将在无精子症男性身上发现基因变异，以确定临床诊断发展的靶点 或者是心理治疗。项目I将使用Charlson共病指数问卷来确定不孕症患者 或者他们的家庭成员有其他总体健康合并症的病史。项目二将确认不孕症-- 在项目I中确定了相关的遗传变异，并表征了生育力和总体健康表型。 项目二还将与项目三合作，以确定表观遗传扰动对 精原干细胞功能。项目III将开发小鼠支持细胞和生殖细胞的基因疗法 无精子症的模型，并将提供关键的安全性和可行性数据，以告知公众关于 生殖系内和生殖系周围基因治疗的风险和好处。试点项目将发现表观遗传学 生育男性与不育男性睾丸生殖细胞和体细胞的图景。核心A将提供 行政监督，促进项目和核心之间的沟通和数据交换，以确保 这一P50计划产生的影响大于其各部分的总和。教育与外展 CORE将通过开发实践教学模块来最大限度地提高本P50课程的公众影响力 中小学生和高中生以及服务不足社区的成年人关于生殖医学的知识 不孕不育的遗传学。模块将在之前在PIT移动科学实验室进行测试和验证 部署到圣路易斯、匹兹堡、伊萨卡和纽约的教师研讨会，允许教师实施 他们教室里的模块。以男性为重点的教学模块也将与P50中心共享 俄勒冈州和西北大学，以补充他们现有的以女性为重点的动手模块。