Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes

遗传性内质网糖尿病的分子遗传学

• 批准号: 10417734
• 负责人: Bohdan Khomtchouk
• 金额: $ 56.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417734
• 关键词: Affect; Anti-Inflammatory Agents; Beta Cell; Bioinformatics; Biological Assay; Calcium; Cardiovascular Diseases; Cell Death; Cell Line; Cell Survival; Cell model; Cell physiology; Cells; Cessation of life; Chemicals; Clinical Data; Complex; Databases; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Epilepsy; Etiology; Failure; Functional disorder; Genes; Genetic; Genetic study; Glucose; Homeostasis; INS gene; Inherited; Insulin; Insulin-Dependent Diabetes Mellitus; Metabolic Diseases; Microcephaly; Modeling; Modification; Molecular; Molecular Chaperones; Molecular Genetics; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Oxidation-Reduction; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Proteins; Regulation; Role; Syndrome; Testing; Therapeutic; Variant; WFS1 gene; Wolcott-Rallison syndrome; Wolfram Syndrome; data ecosystem; design; disease phenotype; efficacy testing; endoplasmic reticulum stress; genetic variant; genetically modified cells; genomic data; induced pluripotent stem cell; insulin secretion; lipid metabolism; mutant; novel; overexpression; precision medicine; protein folding; response; small molecule; therapy design

Abstract The endoplasmic reticulum (ER) is best known for its role as the locus of protein folding, calcium storage, and lipid metabolism. The organelle also integrates numerous other molecular pathways and contributes to cellular calcium homeostasis, reduction-oxidation regulation, and cell death. Given the many vital and complex functions of the ER, it is little wonder that its failure can trigger a range of diseases. It has been shown that dysregulation of ER homeostasis may underlie β cell dysfunction and death in type 1 and type 2 diabetes, as well as in monogenic forms of diabetes, including Wolfram syndrome, Wolcott-Rallison syndrome, microcephaly, epilepsy, and diabetes syndrome (MEDS), and mutant insulin gene-induced diabetes caused by pathogenic variants in the WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes respectively. To further understand the contribution of ER dysfunction to β cell death and design novel treatments targeting ER for diabetes, we need to establish functional studies of gene variants affecting ER homeostasis, design treatments targeting common molecular pathways altered in ER stressed β cells, and identify other ER genes involved in β cell dysfunction and death. In this proposal, we will characterize WFS1 and CISD2, EIF2AK3, IER3IP1, and INS variants using functional assays and bioinformatics and test novel treatments targeting the common molecular pathways altered in β cells expressing pathogenic variants of WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes. Successful completion of this study will lead to the establishment of precision medicine for hereditary ER diabetes.

抽象的 内质网 (ER) 以其作为蛋白质折叠、钙储存和代谢场所的作用而闻名。 脂质代谢。该细胞器还整合了许多其他分子途径，并有助于细胞 钙稳态、氧化还原调节和细胞死亡。鉴于许多重要且复杂的功能 急诊室的故障会引发一系列疾病，这也就不足为奇了。研究表明，失调 ER 稳态的改变可能是 1 型和 2 型糖尿病以及 β 细胞功能障碍和死亡的基础 单基因糖尿病，包括 Wolfram 综合征、Wolcott-Rallison 综合征、小头畸形、癫痫、 和糖尿病综合征（MEDS），以及由胰岛素基因突变引起的致病性变异引起的糖尿病 分别是WFS1和CISD2、EIF2AK3、IER3IP1和INS基因。进一步了解贡献 ER 功能障碍对 β 细胞死亡的影响并设计针对 ER 的糖尿病新疗法，我们需要建立 影响内质网稳态的基因变异的功能研究，设计针对常见分子的治疗方法 ER 应激 β 细胞中通路的改变，并鉴定出与 β 细胞功能障碍和死亡有关的其他 ER 基因。在 在本提案中，我们将使用函数来表征 WFS1 和 CISD2、EIF2AK3、IER3IP1 和 INS 变体 分析和生物信息学，并测试针对 β 细胞中改变的常见分子途径的新疗法 表达 WFS1 和 CISD2、EIF2AK3、IER3IP1 和 INS 基因的致病变异。顺利完成 这项研究将导致遗传性 ER 糖尿病精准医学的建立。