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.

文摘:整体