Functional evaluation of kinesin gene variants associated with female subfertility and egg aneuploidy.

与女性生育力低下和卵子非整倍性相关的驱动蛋白基因变异的功能评估。

基本信息

批准号：
10537275
负责人：
LEELABATI BISWAS
金额：
$ 4.61万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537275
关键词：
Address Affect Age Aneuploidy Biological Assay Biology Candidate Disease Gene Cell division Cells Chromosome Segregation Chromosome abnormality Chromosomes Clinic Clinical Complex Conceptions Coupled Data Data Set Decision Making Defect Development Disease Embryo Ensure Etiology Evaluation Event Faculty Failure Female Female infertility Fertility Fiber Foundations Gametogenesis Genes Genetic Genetic Diseases Genetic Screening Genetic Variation Genomics Goals Habitual Abortion Healthcare Human Genetics Impairment Infertility Institutes Kinesin Kinetics Knock-in Knock-in Mouse Knowledge Length Light Link Maternal Age Maternal-fetal medicine Meiosis Mentors Microscopy Microtubules Modeling Modernization Molecular Molecular Analysis Monitor Morphology Motor Mus Mutation New Jersey Oocytes Outcome Pathogenicity Patients Perinatal Physicians Predisposition Process Proteins Reproduction Reproductive Endocrinology Reproductive Health Research Research Training Resolution Risk Scientist Testing Training Training Programs United States Universities Validation Variant Woman Work advanced maternal age age group arm base career causal variant chromosome number abnormality clinical diagnostics computerized tools design egg exome sequencing experience experimental study female fertility genetic predictors genetic resource genetic testing genetic variant in silico insight live cell imaging mouse model next generation sequencing novel overexpression prognostic protein structure reproductive reproductive system disorder research facility research study subfertility tool

项目摘要

Infertility is a common disease affecting 11% of reproductive-age women in the US. A leading cause of female infertility is egg or embryo aneuploidy. Although aneuploidy rates are coupled to maternal age, aneuploidy rates vary within a given maternal age group. Thus, for some patients, maternal age is an insufficient predictor. Recent evidence suggests that maternal genetic variation confers predisposition to aneuploid conception. However, no genetic test for a woman’s risk of aneuploid conception exists. Therefore, this project’s objective is to identify causal maternal variants for predisposition to aneuploid conception. Using whole-exome sequencing data from women with either high or low rates of aneuploid conception relative to maternal age, we found that variants in genes encoding kinesins are overrepresented in patients with high rates of aneuploid conception. Kinesins, microtubule-associated motor proteins, are promising candidate genes for aneuploidy risk because they are key regulators of chromosome segregation and cell division. I hypothesize that variants in genes encoding kinesins are causal variants in conferring predisposition to aneuploid conception. I will address this hypothesis in Aim 1 by assessing these candidate genetic variants for their ability to cause aneuploidy in mouse eggs and, for those that screen positive, determine the egg development event that is disrupted. I will then evaluate the variants via in silico tools. In Aim 2, I will build upon my preliminary data, which reveal that variants in one candidate gene, KIF18A, cause catastrophic spindle defects in mouse eggs, and I will dissect how the kinesin motor domain of KIF18A contributes to aneuploidy via mouse models and in silico protein structure analysis. These data will facilitate establishment of causal maternal genetic variants in aneuploidy and provide insight into the specific mechanisms of KIF18A motor domain variation in aneuploidy. These studies are the research training arm of a comprehensive training plan that will build a strong foundation for a career as a physician-scientist in women’s reproductive health. Via the proposed research, I will gain experience in rigorous and creative research approaches to egg biology, the molecular basis of female infertility, genetic disease research in mouse models, and computational genomics. This work will be conducted at the Human Genetics Institute of New Jersey, with state-of-the-art microscopy facilities, modern mouse oocyte research facilities, powerful computational genetics resources, and rich faculty expertise. My research experience will be enhanced by targeted advanced training courses in reproduction, high-resolution microscopy, and genomics. The entirety of my training will be coupled to a longitudinal clinical training program including reproductive endocrinology and infertility, perinatal genetics, and maternal-fetal medicine at the state’s largest academic healthcare center, Rutgers University. The mentored research and comprehensive training plan proposed has been carefully designed to build increasing independence for a productive translational reproductive health career.

不育是一种常见的疾病，影响了美国11％的生殖年龄妇女。女性的主要原因尽管非整倍性速率耦合到产妇年龄，但非整倍性费率在给定的产妇年龄组中有所不同。对于某些患者而言，孕产妇的年龄是一个不足的预测指标。最近的证据表明，物质遗传变异承认对非整倍体概念的易感性。但是，没有对女性患有非整倍体概念的风险的基因检测。因此，这个项目是目的是确定因果概念易感性的因果孕产妇变体。使用相对于具有较高或低速率的女性的全外观测序数据孕产妇年龄，我们发现编码驱动蛋白的基因的变体在高的患者中过分占代表性的过多非整倍体概念的速率。驱动蛋白，微管相关的运动蛋白，被保证是候选者非整倍性风险的基因是因为它们是染色体分离和细胞分裂的关键调节剂。我假设编码驱动蛋白的基因中的变体是会议倾向的因果变异非整倍体概念。我将通过评估这些候选遗传变异的AIM 1中的这一假设它们在小鼠卵中引起非整倍性的能力，对于筛选阳性的人，确定卵开发事件被破坏。然后，我将通过计算机工具中评估变体。在AIM 2中，我将建造在我的初步数据上，该数据揭示了一个候选基因KIF18A中的变体引起灾难性的小鼠卵中的主轴缺陷，我将剖析KIF18A的驱动蛋白运动域如何贡献通过小鼠模型和硅蛋白结构分析中的非整倍性。这些数据将有助于建立非整倍性中的因果母体遗传变异，并洞悉KIF18A的特定机制运动域的运动域变化。这些研究是全面培训的研究培训部门计划将为妇女复制健康的身体科学家的职业奠定坚实的基础。通过拟议的研究，我将获得有关卵生物学严格而创造性的研究方法的经验，女性不育症的分子基础，小鼠模型中的遗传疾病研究和计算基因组学。这项工作将在新泽西州人类遗传学研究所进行，并具有最新的显微镜检查设施，现代老鼠卵母细胞研究设施，强大的计算遗传资源和丰富的教师专业知识。有针对性的高级培训课程将增强我的研究经验，高分辨率显微镜和基因组学。我的整个培训将耦合到纵向临床培训计划，包括生殖内分泌学和不孕症，围产期遗传学和母亲遗产该州最大的罗格斯大学学术医疗中心的医学。受过指导的研究和提出的全面培训计划已经过精心设计，以建立越来越多的独立性生产性翻译的生殖健康职业。