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：
10615191
负责人：
Bohdan Khomtchouk
金额：
$ 54.81万
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/10615191
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 Metabolic Diseases Microcephaly Modeling Modification Molecular Molecular Chaperones Molecular Genetics Mutate Mutation Organelles 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 oxidation precision medicine protein folding response small molecule therapy design type I and type II diabetes

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.

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。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具有许多重要且复杂的功能。 ER 的失调会引发一系列疾病也就不足为奇了。 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研究 WFS1 和 CISD2、EIF2AK3、IER3IP1 和 INS 基因，以进一步了解其贡献。 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，针对常见分子设计治疗方法改变 ER 应激 β 细胞的通路，并鉴定与 β 细胞功能障碍和死亡有关的其他 ER 基因。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。这项研究将导致遗传性 ER 糖尿病精准医学的建立。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CETP and SGLT2 inhibitor combination therapy improves glycemic control.

CETP 和 SGLT2 抑制剂联合治疗可改善血糖控制。

DOI：
10.1101/2023.06.13.23291357
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Khomtchouk,BohdanB;Sun,Patrick;Ditmarsch,Marc;Kastelein,JohnJP;Davidson,MichaelH
通讯作者：
Davidson,MichaelH

Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.

DOI：
10.1016/j.ymthe.2023.04.020
发表时间：
2023-06-07
期刊：
MOLECULAR THERAPY
影响因子：
12.4
作者：
Winter, Hanna;Winski, Greg;Busch, Albert;Chernogubova, Ekaterina;Fasolo, Francesca;Wu, Zhiyuan;Baecklund, Alexandra;Khomtchouk, Bohdan B.;Booven, Derek J. Van;Sachs, Nadja;Eckstein, Hans-Henning;Wittig, Ilka;Boon, Reinier A.;Jin, Hong;Maegdefessel, Lars
通讯作者：
Maegdefessel, Lars

Machine learning classifiers predict key genomic and evolutionary traits across the kingdoms of life.