Epigenetics and Genetics of Infertility and Associated Comorbidities

不孕症及相关合并症的表观遗传学和遗传学

• 批准号: 10613343
• 负责人: John C Schimenti
• 金额: $ 34.81万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613343
• 关键词: Address; Affect; Age; Alleles; Area; Bioinformatics; Biological Assay; Biological Models; CRISPR interference; CRISPR-mediated transcriptional activation; Cardiovascular Diseases; Cell Compartmentation; Cell Maintenance; Cell Reprogramming; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Computing Methodologies; DNA Modification Process; Data; Detection; Development; Disease; Double Strand Break Repair; Down Syndrome; Enzymes; Epigenetic Process; Family; Fanconi' s Anemia; Fertility; Future; Gametogenesis; Gene Expression Profile; Gene Modified; Genes; Genetic; Genetic Transcription; Genome; Genomic approach; Goals; Guide RNA; Health; Home; Human; Impairment; Incidence; Individual; Infertility; Knowledge; Lentivirus; Lesion; Libraries; Literature; Long QT Syndrome; Male Infertility; Malignant Neoplasms; Meiosis; Methyltransferase; Mining; Modeling; Modernization; Modification; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Mutate; Mutation; Natural regeneration; Obesity; Patients; Persons; Phenotype; Population; Predisposition; Process; Proliferating; RNA; Reproduction; Reproductive system; Role; Sertoli cell only syndrome; Somatic Cell; Sperm Motility; Spermatogenesis; Statistical Methods; Technology; Testing; Testis; Thyroid Gland; Tissues; Training; Validation; Variant; candidate identification; candidate validation; cohort; comorbidity; computerized tools; design; genetic variant; genome editing; health management; histone modification; human male; improved; induced pluripotent stem cell; male; mouse model; mutant; non-genetic; novel; novel strategies; prevent; receptor; reproductive; stem; stem cells; stemness; subfertility; transcriptomics

PROJECT SUMMARY Despite extensive knowledge of genes required for gametogenesis, the causes of most human infertilities are unknown. It is thought that about half of cases have a genetic basis, but it remains problematic to definitively identify the exact genetic lesion(s) that may be responsible in a given person, even with genome sequence information. Given the indications that certain genetically-based causes of infertility are associated with comorbidities, and the high incidence of infertility in the population, it would be of substantial clinical impact to make progress towards reliably identifying molecular causes of infertility. The roots of non-genetic causes are even more difficult to ascertain, but epigenetic alterations may underlie certain types of infertility, particularly in males where such alterations may occur in spermatogonial stem cells (SSCs). Project II has 3 Specific Aims that seek to address these important issues in the field. Aim 1 is to functionally validate candidate genetic variants identified from infertility patient cohorts and families in Project 1. This will be done by modeling the variants in CRISPR-modified mice, then phenotyping the mice for not only reproductive phenotypes, but also comorbidities that may exist in the corresponding patients, such as obesity, cancer susceptibility, or cardiovascular disease. Aim 2 is to characterize mutations that cause infertility or subfertility phenotypes in mice, and which may have comorbidities that have yet to be recognized. An emphasis will be on genes that are expressed in somatic tissues in addition to the testis. Aim 3 employs a novel approach to identify epigenetic alterations that impact SSCs, potentially leading to Sertoli Cell Only syndrome (SCOS) and non-reproductive phenotypes. This approach involves CRISPR inhibition and activation technologies to conduct a screen of known epigenetic modification genes that impact the efficiency somatic cell reprogramming and SSC maintenance. In sum, this project uses diverse, cutting-edge strategies to improve the accuracy and discovery of genetic and epigenetic causes of human male infertility and related comorbidities.

项目摘要 尽管对配子发生所需的基因有广泛的了解，但大多数人类不育的原因是 未知据认为，大约一半的病例有遗传基础，但它仍然是一个问题，以明确 确定确切的遗传病变，可能是在一个给定的人，甚至与基因组序列负责 信息.鉴于某些基于遗传的不孕症原因与 合并症，以及人群中不孕症的高发病率，这将对临床产生重大影响， 在可靠地确定不孕症的分子原因方面取得进展。非遗传原因的根源是 甚至更难确定，但表观遗传改变可能是某些类型不育的基础，特别是在 雄性，其中这种改变可能发生在精原干细胞（SSC）中。项目二有三个具体目标 来解决这些重要的实地问题。目的1是功能验证候选基因 从项目1中的不孕症患者队列和家庭中鉴定出的变异。这将通过对 CRISPR修饰小鼠中的变异，然后对小鼠进行表型分析，不仅用于生殖表型， 相应患者中可能存在的合并症，如肥胖、癌症易感性或 心血管疾病目的2是鉴定导致不育或低生育力表型的突变， 小鼠，并且其可能具有尚待识别的共病。重点将放在基因上， 除了睾丸外，还在体细胞组织中表达。AIM3采用了一种新的方法来识别表观遗传 影响SSC的改变，可能导致支持细胞综合征（SCOS）和非生殖性 表型这种方法涉及CRISPR抑制和激活技术，以进行筛选。 影响体细胞重编程和SSC效率的已知表观遗传修饰基因 上维护总而言之，该项目使用多种尖端策略来提高准确性和发现率。 人类男性不育症和相关共病的遗传和表观遗传原因。