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Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes

遗传性内质网糖尿病的分子遗传学

基本信息

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
项目类别：
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

项目摘要

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.

摘要