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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.

不孕症是一种常见疾病，影响美国11%的育龄妇女。女性的主要原因不育是卵子或胚胎的非整倍性。虽然非整倍体发生率与母亲年龄有关，在某一产妇年龄组内，这一比率各不相同。因此，对于一些患者，母亲年龄是一个不足的预测。最近的证据表明，母体遗传变异赋予非整倍体受孕的倾向。然而，目前还没有针对女性非整倍体受孕风险的基因检测。因此，该项目的目的是鉴定非整倍体妊娠易感性的母体变异。使用来自非整倍体受孕率高或低的女性的全外显子组测序数据，我们发现编码驱动蛋白的基因变异在高血压患者中的比例过高，非整倍体受孕率。驱动蛋白是一种微管相关的运动蛋白，是一种很有前途的候选蛋白非整倍体风险的基因，因为它们是染色体分离和细胞分裂的关键调节因子。我假设编码驱动蛋白的基因中的变体是赋予易感性的因果变体，非整倍体受孕我将在目标1中通过评估这些候选遗传变异来解决这一假设，它们在小鼠卵细胞中引起非整倍体的能力，对于那些筛选阳性的，被破坏的发展事件。然后，我将通过计算机工具评估变体。在目标2中，我将建立我的初步数据显示，一个候选基因KIF 18 A的变异，我将详细分析KIF 18 A的驱动蛋白运动域是如何影响小鼠卵细胞纺锤体缺陷的，通过小鼠模型和计算机蛋白质结构分析确定非整倍性。这些数据将有助于建立非整倍体中的因果母体遗传变异，并提供对KIF 18 A的具体机制的见解非整倍体中的运动域变异。这些研究都是对训练臂的综合训练的研究该计划将为妇女生殖健康领域的医生-科学家职业生涯奠定坚实的基础。经由在拟议的研究中，我将获得鸡蛋生物学严谨和创造性研究方法的经验，女性不孕症的分子基础、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的人类遗传学研究所进行，使用最先进的显微镜现代化的小鼠卵母细胞研究设施，强大的计算遗传学资源和丰富的师资力量，专业知识我的研究经验将通过有针对性的生殖高级培训课程得到加强，高分辨率显微镜和基因组学。我的整个训练将与一个纵向临床培训计划，包括生殖内分泌学和不孕症，围产期遗传学和母胎在该州最大的学术医疗保健中心罗格斯大学的医学。指导研究和拟议的全面培训计划经过精心设计，富有成效的转化生殖健康事业。