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Develop a human liver system to study SLC25A13 mutations in citrin deficiency

开发人类肝脏系统来研究柠檬酸缺乏症中的 SLC25A13 突变

基本信息

批准号：
10724616
负责人：
Xianfang Wu
金额：
$ 16.1万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10724616
关键词：
3-Dimensional Age of Onset Applications Grants Area Arginine Aspartate Binding Biochemical CD7 gene CD8B1 gene CRISPR/Cas technology Carbohydrates Case Study Cell Communication Cell Line Cells Cellularity Chemicals Child Cholestasis Citrullinemia Clinical Coculture Techniques Data Development Diet Disease Dissection Dyslipidemias Encephalopathies Ethnic Origin Failure Failure to Thrive Frequencies Gene Expression Regulation Genes Genetic Glutamates Glycerol-3-Phosphate Dehydrogenase Glycolysis Goals Growth Hepatic Hepatic Stellate Cell Hepatocyte Heterozygote Homozygote Human Hyperammonemia Impairment In Vitro Individual Intervention Japan Knock-out Knockout Mice Laboratories Lead Liver Macrophage Malates Medium chain triglycerides Mitochondria Modeling Mutation Mutation Detection NADH Neonatal Oils Outcome Pathogenesis Patient-Focused Outcomes Patients Penetrance Pharmaceutical Preparations Phenotype Pyruvate Rare Diseases Reporting Research Risk Factors Side Sodium Study models System Testing Therapeutic Therapeutic Intervention age related autosome citrin clinically relevant dietary disease phenotype effective therapy experimental study hemodynamics in vivo induced pluripotent stem cell loss of function loss of function mutation pluripotency therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY Citrin deficiency (CD), an autosomal recessive disorder caused by mutations in SLC25A13 gene, is a pan-ethnic rare disease. Currently there is no specific drug for CD. Dietary management is regarded as the most effective treatment for CD, as well as a decisive factor in the clinical outcome of patients. However, dietary management has only been based on small case reports and dietary management for children with CD is generally poor, especially in areas where carbohydrate-based diets are predominant. Thus, further research is needed to understand disease pathogenesis and facilitate more specific therapeutic development. CD manifests as age-dependent phenotypes and can have severe clinical outcome including failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and citrullinemia type 2 (CTLN2) with a sudden development of hyperammonemic encephalopathy, as well as other clinical manifestations. However, the mechanisms by which how SLC25A13 loss-of-function leads to the abovementioned disease phenotypes remain largely unclear. It also remains poorly understood how the age of onset and incomplete penetrance seen in CD patients are determined. A major unmet need in the study of CD is the lack of a reliable human-relevant model that mimics the entire spectrum of this disease in humans. So far, the only available models to study CD are the knockout (KO) mice (i.e., Slc25a13-KO and Slc25a13 and Gpd2-double KO). Owing to marked species-specific differences in gene regulation especially in glycolysis, the utility and clinical relevance of these models are debated. The need for human-relevant system is further underscored by the observations showing variable age of onset and incomplete penetrance seen in CTLN2 patients where additional environmental and/or genetic triggers are suspected. The primary research goal of this application is to leverage a human induced pluripotent stem cell (iPSC)- derived multicellular in vitro liver model developed in our laboratory to create a human-relevant model for studying SLC25A13 in CD. Across the two specific aims, we plan to generate liver cultures harboring wild-type or SLC25A13 KO cells and to characterize the possible disease phenotypes that are relevant to human CD. Developing an iPSC-derived renewable and genetically manipulatable human system for the study of SLC25A13 in CD will facilitate the detailed dissection of disease pathogenesis. Moreover, given the lack of suitable human- relevant systems to study CD, our iPSC-derived platform will provide an urgently needed new platform to test interventions and promote the development of specific therapeutics. Finally, this initial support will allow us to perform pilot analysis and characterization and to acquire critical preliminary data for a bigger grant application that will facilitate these efforts.

项目总结