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.

项目概要/摘要 CLPB 基因的遗传性双等位基因突变是先天性中性粒细胞减少症的原因与 MEGCANN 相关，这是一种罕见的常染色体隐性遗传病（OMIM 条目#616271）。在其严重的话，这种疾病会导致几个月大时因严重的神经系统损害而死亡症状或危及生命的感染。最近发现的从头单等位基因突变 CLPB基因以显性失活方式发挥作用，也会导致严重的先天性中性粒细胞减少症。 CLPB基因编码一种广泛表达的线粒体蛋白，含有多种锚蛋白重复序列和单个 AAA+（与多种细胞活动相关的 ATP 酶）模块。这中性粒细胞前体细胞 CLPB 功能的分子机制尚不清楚，突变的 CLPB 变异引起的线粒体缺陷及其与粒细胞生成缺陷的联系定义不明确。我们假设 CLPB 对于糖酵解的代谢转变至关重要中性粒细胞分化过程中线粒体呼吸的影响。我们将通过以下方式检验这个假设完成两个具体目标。在目标 1 中，我们将确定 CLPB 在线粒体中的作用使用成髓细胞系模型的形态、代谢和中性粒细胞分化粒细胞生成。该目标将检验 CLPB 在以下方面发挥重要作用的子假设：中性粒细胞分化过程中的线粒体重塑和代谢重编程。瞄准 2、我们将研究疾病突变对CLPB和关键药物之间相互作用的影响线粒体动力学和嵴形态的调节因子。这个目标将测试子假设双等位基因突变与单等位基因突变的影响之间的主要区别对 CLPB 活性的影响源于突变 CLPB 变体的不同相互作用倾向。最终，我们的研究将为 CLPB 在中性粒细胞中的作用提供新的见解。分化，将有助于了解疾病 CLPB 变异的分子缺陷，并将为开发 CLPB 突变引起的中性粒细胞减少症的潜在治疗方法奠定了基础。