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

基本信息

批准号：
10379349
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
项目类别：
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/10379349
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 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&apos 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 Plant Roots Play Population Predisposition Process RNA Reproduction Reproductive system Role Sertoli cell only syndrome Somatic Cell Sperm Motility Spermatogenesis Statistical Methods Sum Technology Testing Testis Thyroid Gland Tissues Training Validation Variant base 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

项目摘要

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.

项目概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，但要明确这一点仍然存在问题。即使有基因组序列，也能识别出可能对特定人造成影响的确切遗传病变信息。鉴于有迹象表明某些基于遗传的不孕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识别不孕不育的分子原因方面取得进展。非遗传原因的根源是更难以确定，但表观遗传改变可能是某些类型不孕症的基础，特别是在男性的精原干细胞（SSC）可能发生这种改变。项目 II 有 3 个具体目标力求解决该领域的这些重要问题。目标 1 是功能验证候选基因从项目 1 中的不孕症患者群体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，不仅包括生殖表型，还包括相应患者可能存在的合并症，例如肥胖、癌症易感性或心血管疾病。目标 2 是确定导致不孕或生育力低下表型的突变的特征小鼠，并且可能存在尚未识别的合并症。重点将放在基因上除睾丸外，还在体组织中表达。目标 3 采用一种新颖的方法来识别表观遗传影响 SSC 的改变，可能导致仅支持细胞综合征 (SCOS) 和非生殖表型。该方法涉及 CRISPR 抑制和激活技术来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维护。总而言之，该项目使用多样化、前沿的策略来提高准确性和发现率人类男性不育症和相关合并症的遗传和表观遗传原因。