Discovery and Annotation of Targets for Gene Therapy of Infertile Men

不育男性基因治疗靶点的发现和注释

基本信息

批准号：
10613341
负责人：
DONALD F. CONRAD
金额：
$ 63.91万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613341
关键词：
Address Affect Age Assisted Reproductive Technology Atlases Cells Clinic Clinical Communities Computer Analysis Couples Cytogenetics Data Databases Diagnosis Dideoxy Chain Termination DNA Sequencing Disease Embryo Endocrine Exclusion Criteria Failure Family Functional disorder Gene Expression Genes Genetic Genetic Services Genetic Variation Genome Genomics Geography Goals Haplotypes Health Heritability Histology Hospitals Human Impairment Individual Infertility Informatics Internet Joints Location Male Infertility Maps Medical Genetics Medical Records Methodology Modernization Mus Mutate Mutation Other Genetics Outcome Pathology Patient Recruitments Patient Selection Patients Pattern Phenotype Population Population Control Pregnancy Pregnancy loss Preimplantation Diagnosis Probability Samples Protein Databases Proteins Protocols documentation Publications Publishing Recurrence Reproductive Endocrinology Reproductive Medicine Research Personnel Resolution Risk Sampling Sequence Tagged Sites Site Specialist Statistical Methods Technology Testing Tissues Universities Validation Variant Visit Washington Work causal variant cell type cohort comorbidity comorbidity Index comparative genomic hybridization cost density exome gene interaction gene therapy genetic technology genetic testing genetic variant genome sequencing genome wide association study genome-wide genomic tools genotyped patients identity by descent infertility treatment insertion/deletion mutation instrument knowledge base medical schools men model organism model organisms databases mutant participant enrollment patient registry prospective protein expression reproductive sample archive single-cell RNA sequencing targeted treatment tool trait transcriptome sequencing whole genome

项目摘要

Abstract: Project I: Discovery and Annotation of Targets for Gene Therapy of Infertile Men Infertility affects 15% of reproductive-age couples in the US, leading to more than 108,000 new visits to reproductive endocrinology and infertility (REI) clinics per year. Nearly all such clinics offer pre-implantation genetic diagnosis of embryos and genetic testing for known mutations associated with endocrine dysfunction, primary gonadal failure, and recurrent pregnancy loss. However, reproductive medicine specialists rely on old technologies like cytogenetics, sequence-tagged site PCR, and Sanger sequencing for these tests and are not taking advantage of modern whole-genome and RNA sequencing technologies common in clinical genetics of other disease states. New genomic tools, both computational and experimental, promise to revolutionize the way we diagnose and treat infertility. An overall goal of this P50 application is to create a roadmap for how these tools can be used to (a) identify mutations contributing to male infertility, (b) characterize how these mutations may contribute to pathology in somatic tissues, and (c) how gene therapy can be used to treat these pathologies in a safe and targeted manner. In this project, we are recruiting patients of male infertility from three primary sites: Washington University, Weill Cornell Medical School, and Magee-Womens Hospital. We will apply whole- genome sequencing and high-resolution array CGH to map the location of genetic variation in 500 total cases, including 21 large, multiplex families with heritable forms of azoospermia. As part of the patient phenotyping, we will deploy a specialized instrument known as the Charlson Comorbidity index to specifically document the evidence for comorbidity in each case of infertility. We will develop and apply highly sensitive statistical methods, which draw upon the information in massive population control databases, to identify statistically unusual mutations that are likely to confer risk for spermatogenic impairment. We will develop knowledge bases that summarize the evidence from model organisms that these mutations can cause pathology in both gonadal and somatic tissues. And we will attempt to infer the testicular cell type(s) that are the primary sites of pathology for each mutation, to help guide the targeting of gene therapy. The most important long-term outcome of this work will be the publication of analysis tools and knowledge bases that will facilitate the use of genome sequencing in the treatment of infertility. Combined with the results from Project II and Project III, our results will give reproductive medicine specialists a roadmap for the use of modern genetic technologies to investigate and treat infertility.

摘要：项目I：对不育男人基因治疗的靶标的发现和注释不孕症影响美国15％每年生殖内分泌学和不孕症（REI）诊所。几乎所有此类诊所都提供植入前胚胎的遗传诊断和与内分泌功能障碍相关的已知突变的基因检测，原发性性腺衰竭和复发性妊娠丧失。但是，生殖医学专家依靠旧这些测试的技术，诸如细胞遗传学，序列标记的位点PCR和Sanger测序，不是利用现代的全基因组和RNA测序技术在临床遗传学中常见的技术其他疾病状态。计算和实验性的新基因组工具有望彻底改变我们诊断和治疗不孕症。该P50应用程序的总体目标是为如何使用这些工具创建路线图（a）识别有助于男性不育症的突变，（b）表征这些突变如何有助于体细胞组织中的病理学，以及（c）如何使用基因治疗来治疗这些病理学有针对性的方式。在这个项目中，我们正在从三个主要部位招募男性不孕症患者：华盛顿大学，威尔·康奈尔医学院和马吉·沃蒙斯医院。我们将应用整个基因组测序和高分辨率阵列CGH以绘制500例总病例的遗传变异位置，包括21个具有遗传形式的Azoospermia的大型多重家族。作为患者表型的一部分，我们将部署一种名为Charlson合并症指数的专业工具，以专门记录在每种不孕症情况下合并症的证据。我们将开发并应用高度敏感的统计借助大量人口控制数据库中信息的方法，以统计确定可能赋予生精性损害风险的异常突变。我们将发展知识总结了模型生物的证据的基础，即这些突变都会在两者中引起病理性腺和躯体组织。我们将尝试推断是睾丸细胞类型，这些细胞类型是每种突变的病理学，以帮助指导基因疗法的靶向。这项工作最重要的长期结果将是出版分析工具和知识将促进基因组测序在不孕症治疗中的基础。结合结果从项目II和III项目中，我们的结果将为生殖医学专家提供使用的路线图现代遗传技术调查和治疗不育症。