Hyperglycemia in Turner syndrome: Mechanisms and X chromosome contributions

项目总结/摘要 特纳综合征（Turner syndrome，TS）是一种常见的X染色体（Xchr）异常引起的遗传性疾病。妇女 TS患者患糖尿病（DM）的风险是普通人群的四倍， 对死亡率有很大影响。尽管TS中DM的患病率，但其潜在机制和 驱动糖尿病风险的特定Xchr贡献仍然难以捉摸。因此，没有具体的预防措施。 策略或治疗TS中的DM。拟议项目的目标是解开基因和 导致TS高血糖症的生理机制，在Xchr背景下使用血糖表型 基因剂量、Xchr亲本来源以及基因组和表观遗传技术。我的主要假设是 TS相关高血糖症是Xchr基因剂量改变的结果（例如，通过Xchr印记和/或 结构Xchr变异），并且这有助于进行性β细胞功能的TS特异性表型 首先检测到的损伤仅响应于口服葡萄糖而不是混合的大量营养素。测试这些 假设，我们提出以下目标：（1）确定Xchr的贡献TS高血糖表型 和（2）确定β细胞功能是否响应TS中的混合大量营养素而受损。我们将执行 对国家儿童健康和人类发展研究所数据的多变量分析 标本中心，其中包括频繁采样的口服葡萄糖耐量试验（fsOGTT）和Xchr父母- 84例TS患者的来源，以确定是否存在Xchr来源亲本效应， - 是的此外，我们还将招募30名TS患者， RNA测序。这将允许鉴定候选印记Xchr基因。该项目还包括 对20名TS患者和10名年龄、性别和BMI- 匹配的对照以进一步阐明β细胞功能中的TS特异性损伤。完成建议 该项目将有助于了解Xchr对TS高血糖表型的贡献，并有助于 确定药物靶点和/或新的疾病管理策略。这个项目对我来说也是一个工具 通过为我提供血糖表型、基因组学和生物学方面的专业知识， 和表观遗传学技术，多变量统计，以及多中心研究设计和执行。拟议 综合研究，指导，教学培训计划与合作研究相结合 环境在爱荷华州大学和场外合作与教师在明尼苏达大学和 印第安纳州大学将培养我成为一名独立调查员的长期职业目标， 转化研究计划的重点是分离基因组和表观遗传对糖尿病风险的贡献。

PROJECT SUMMARY/ABSTRACT Turner syndrome (TS) is a common genetic disorder caused by X chromosome (Xchr) abnormalities. Women with TS have a four-fold higher risk of developing diabetes mellitus (DM) than the general population, and DM contributes significantly to mortality. Despite the prevalence of DM in TS, the underlying mechanism(s) and specific Xchr contributions driving diabetes risk remain elusive. As such, there are no specific preventative strategies or treatments for DM in TS. The objective of the proposed project is to unravel the genetic and physiologic mechanism(s) that lead to hyperglycemia in TS, using glycemic phenotyping in the context of Xchr gene dosage, Xchr parent-of-origin, and genomic and epigenetic techniques. My central hypotheses are that TS-associated hyperglycemia is a consequence of altered Xchr gene dosage (e.g., by Xchr imprinting and/or structural Xchr variation) and that this contributes to a TS-specific phenotype of progressive beta cell functional impairments first detectable only in response to oral glucose but not mixed macronutrients. To test these hypotheses, we propose the following aims: (1) Identify Xchr contributions to the TS hyperglycemia phenotype and (2) Determine if beta cell function is impaired in response to mixed macronutrients in TS. We will perform multivariable analysis of data from National Institute of Child Health and Human Development’s Data and Specimen Hub, which includes frequently sampled oral glucose tolerance tests (fsOGTT) and Xchr parent-of- origin for 84 individuals with TS to determine if an Xchr parent-of-origin effect exists with respect to categorical glycemia. Additionally, we will enroll 30 individuals with TS to undergo long-read Xchr sequencing in conjunction with RNA sequencing. This will allow identification of candidate imprinted Xchr genes. This project also includes paired fsOGTT and mixed meal tolerance tests (MMTT) for 20 individuals with TS and 10 age-, sex-, and BMI- matched controls to further elucidate TS-specific impairments in beta cell function. Completion of the proposed project will add to understanding of Xchr contributions to the TS hyperglycemia phenotype and contribute toward identification of drug targets and/or new disease managements strategies. The project is also a vehicle for me to achieve my career goals and objectives by providing me with expertise in glycemic phenotyping, genomic and epigenetic techniques, multivariable statistics, and multisite study design and execution. The proposed integrated research, mentorship, and didactic training program combined with the collaborative research environment at the University of Iowa and off-site collaboration with faculty at the University of Minnesota and Indiana University will foster my long-term career goal of becoming an independent investigator leading a translational research program focused on isolating genomic and epigenetic contributions to diabetes risk.