The role of the primary cilium in insulin signaling and common disease pathogenesis

初级纤毛在胰岛素信号传导和常见疾病发病机制中的作用

基本信息

批准号：
10301890
负责人：
Theodore George Drivas
金额：
$ 16.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2025-05-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301890
关键词：
Address Affect Award Bioinformatics Biological Biological Assay Biology Body mass index Candidate Disease Gene Caring Cell Surface Receptors Cell model Cell physiology Cells Cellular biology Cilia Clinic Clinical Code Complex Coupled Data Data Set Development Diabetes Mellitus Diet Disease Disease Pathway Disease model Doctor of Philosophy Electronic Health Record Explosion Foundations Functional disorder Gene Expression General Population Genes Genetic Genetic Diseases Genetic Variation Genomics Glucose Glycosylated hemoglobin A Goals Human Genetics Impairment Individual Institution Insulin Insulin Receptor Investigation Knock-out Knowledge Link Medicine Mendelian disorder Mentorship Methodology Microscopy Modality Modeling Molecular Mutation Non-Insulin-Dependent Diabetes Mellitus Organelles Pathogenesis Pathology Pathway interactions Patient risk Patients Pediatric Hospitals Pennsylvania Persons Pharmaceutical Preparations Phenotype Philadelphia Physicians Positioning Attribute Public Health Receptor Signaling Research Resources Risk Risk Assessment Role Scientist Secure Signal Pathway Signal Transduction Solid Structure of ciliary processes Syndrome Techniques Testing Training Universities Variant Work biobank blood glucose regulation career ciliopathy cohort diabetes risk disease phenotype genetic variant human disease insulin signaling knock-down live cell imaging new therapeutic target novel phenome rare variant response trafficking transcriptome sequencing

项目摘要

PROJECT SUMMARY Rare genetic defects of the primary cilium can cause a number of phenotypically-overlapping Mendelian syndromes, known as ciliopathies. Intriguingly, many ciliopathy patients show signs of impaired glucose homeostasis, with accumulating evidence suggesting that insulin receptor must be specifically trafficked into the cilium to initiate insulin-dependent signaling cascades. However, we do not yet know if variants in ciliary genes increase an individual’s risk for diabetes more generally, nor do we understand the mechanisms by which ciliary genes might affect insulin receptor signaling to cause pathology. The goal of this proposal is to fill this gap in our knowledge using complementary bioinformatic and cell biologic approaches. My clinical and scientific expertise in ciliary biology and human genetics, coupled with my exciting preliminary results, rigorous research plan, and outstanding mentorship team, provide a solid foundation for this project. In completing the proposed work, specifically with its focus on providing me additional training in the field of bioinformatics and in lab management, I will be perfectly poised to begin my independent academic career as a physician scientist seeking to better understand the genetics and biology of ciliary dysfunction in human disease. I have secured the complete support of my institution, and will benefit greatly from the unparalleled resources and mentorship available at both the University of Pennsylvania and the Children’s Hospital of Philadelphia over the course of this award. I hypothesize that variants in ciliary genes increase risk for diabetes by perturbing cell signaling pathways essential to normal insulin signaling. My preliminary analyses in the UK and Penn Medicine Biobanks have already identified numerous ciliary genes and variants significantly associated with glucose and hemoglobin A1c levels, and demonstrate significant changes in ciliary gene expression in response to insulin. I will further investigate these associations with two complementary sets of analyses. Specifically, I will (1) use bioinformatic approaches in large patient datasets to identify and characterize ciliary genes and pathways that confer increased risk for type 2 diabetes phenotypes and (2) validate these findings in cell models of disease, with a specific focus on understanding how genetic variation in ciliary genes perturbs the ciliary transport and downstream signaling of insulin receptor. Through the careful use of cell and molecular biologic approaches including signaling assays, RNAseq, and live cell imaging, I will quantify differences in insulin receptor signaling and ciliary transport of insulin receptor when individual ciliary candidate genes, identified in Aim 1, are knocked down in cell models. The completion of the proposed work will advance our knowledge of cilium biology and common disease genetics, open new avenues for patient risk assessment, and has the potential to identify novel therapeutic targets for the treatment of diabetes. Additionally, the application of the methodology and paradigm developed in this plan will undoubtedly help with the elucidation of multiple other common disease mechanisms attributable to Mendelian disease genes and cellular processes both within and outside of the cilium.

项目概要初级纤毛的罕见遗传缺陷可导致许多表型重叠的孟德尔现象综合征，称为纤毛病，有趣的是，许多纤毛病患者表现出血糖受损的迹象。体内平衡，越来越多的证据表明胰岛素受体必须被专门运输到然而，我们尚不清楚纤毛基因是否存在变异。更普遍地增加个体患糖尿病的风险，我们也不了解睫状体的机制基因可能会影响胰岛素受体信号传导以引起病理学该提案的目标是填补我们的这一空白。使用互补的生物信息和细胞生物学方法的知识。在睫状生物学和人类遗传学方面，加上我令人兴奋的初步结果、严谨的研究计划，以及优秀的导师团队，为完成本项目提供了坚实的基础，特别是它的重点是为我提供生物信息学和实验室管理领域的额外培训，我将完全准备好开始我作为一名医师科学家的独立学术生涯，寻求更好的了解人类疾病中纤毛功能障碍的遗传学和生物学，我已经获得了完全的支持。我的机构的，并将大大受益于两个机构提供的无与伦比的资源和指导宾夕法尼亚大学和费城儿童医院在该奖项的过程中。我发现纤毛基因的变异会通过扰乱细胞信号通路来增加患糖尿病的风险我在英国和 Penn Medicine Biobanks 进行的初步分析表明，这对于正常的胰岛素信号传导至关重要。已经鉴定出许多纤毛基因，并与葡萄糖和血红蛋白 A1c 显着相关水平，并证明纤毛基因表达对胰岛素的反应发生显着变化，我将进一步证明。具体来说，我将（1）使用生物信息学来研究这些关联。在大型患者数据集中识别和表征睫状基因和通路的方法 2 型糖尿病表型的风险增加，并且 (2) 在疾病细胞模型中验证这些发现特别关注了解纤毛基因的遗传变异如何扰乱纤毛运输和通过仔细使用细胞和分子生物学方法，胰岛素受体的下游信号传导。包括信号分析、RNAseq 和活细胞成像，我将量化胰岛素受体信号传导的差异当目标 1 中确定的单个纤毛候选基因被敲除时，胰岛素受体的纤毛转运细胞模型中所提出的工作的完成将增进我们对纤毛生物学和常见疾病遗传学，为患者风险评估开辟新途径，并有可能识别新的此外，还包括治疗糖尿病的治疗目标、方法和范例的应用。该计划中制定的无疑将有助于阐明多种其他常见疾病机制可归因于孟德尔疾病基因和纤毛内外的细胞过程。