权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanistic links between mutations in the CLPB gene and congenital neutropenia

CLPB基因突变与先天性中性粒细胞减少症之间的机制联系

基本信息

批准号：
10526864
负责人：
Anna Zolkiewska
金额：
$ 24.25万
依托单位：
KANSAS STATE 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：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526864
关键词：
ATP phosphohydrolase Age-Months Ankyrin Repeat Apoptosis Biological Assay CRISPR/Cas technology Cataract Cell Line Cells Cessation of life Co-Immunoprecipitations Consumption Crista ampullaris Defect Development Disease Dominant-Negative Mutation Energy Metabolism Fatty Acids Future Gene Expression Gene Targeting Genes Glucose Glycolysis Goals Granulopoiesis HL60 Health Hereditary Disease Human Immunity Immunologic Deficiency Syndromes Immunologics Impairment In Vitro Individual Infection Inherited International Investigation Life Link Measures Membrane Potentials Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Weight Morphology Mus Mutate Mutation Neurologic Neurologic Symptoms Neutropenia OPA1 gene Online Mendelian Inheritance In Man Outcome Oxidative Phosphorylation Oxygen Consumption Pathogenicity Physiology Play Production Progranulocytes Recombinants Regulation Research Respiration Role Societies Structure Testing Variant acute myeloid leukemia cell base biophysical techniques congenital immunodeficiency granulocyte insight interest mitochondrial membrane mitochondrial metabolism mutant neutrophil novel precursor cell preservation prohibitin protein complex response

项目摘要

PROJECT SUMMARY/ABSTRACT Hereditary biallelic mutations in the CLPB gene are the cause of congenital neutropenia associated with MEGCANN, a rare autosomal recessive disease (OMIM entry #616271). In its severe form, the disease leads to death by a few months of age as a result of significant neurologic symptoms or life-threatening infections. Recently identified de novo monoallelic mutations in the CLPB gene act in a dominant-negative manner and also cause severe congenital neutropenia. The CLPB gene encodes a broadly expressed mitochondrial protein containing several ankyrin repeats and a single AAA+ (ATPases Associated with diverse cellular Activities) module. The molecular mechanism of CLPB function in neutrophil precursor cells is not known, and the mitochondrial defects elicited by mutated CLPB variants and their link to defective granulopoiesis are poorly defined. We hypothesize that CLPB is essential for the metabolic shift from glycolysis to mitochondrial respiration during neutrophil differentiation. We will test this hypothesis by completing two Specific Aims. In Aim 1, we will determine the role of CLPB in mitochondrial morphology, metabolism, and neutrophil differentiation using myeloblastic cell line models of granulopoiesis. This Aim will test the sub-hypothesis that CLPB plays an essential role in mitochondrial remodeling and metabolic reprogramming during neutrophil differentiation. In Aim 2, we will examine the effect of disease mutations on the interactions between CLPB and key regulators of mitochondrial dynamics and cristae morphology. This Aim will test the sub- hypothesis that the principal difference between the effects of biallelic vs. monoallelic mutations on the CLPB activity arises from distinct interaction propensities of the mutated CLPB variants. At the outcome, our studies will provide a new insight into the role of CLPB in neutrophil differentiation, will help understand the molecular defects of the disease CLPB variants, and will set the stage for developing potential treatments for neutropenias caused by CLPB mutations.

项目总结/文摘