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

• 批准号: 10630259
• 负责人: Anna Zolkiewska
• 金额: $ 19.14万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630259
• 关键词: ATP phosphohydrolase; Age Months; Alleles; 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; Exclusion; Fatty Acids; Future; Gene Expression; Gene Targeting; Genes; Glucose; Glycolysis; Goals; Granulopoiesis; HL60; Health; Hereditary Disease; Heterozygote; 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; autosome; biophysical techniques; congenital immunodeficiency; genetic variant; granulocyte; insight; interest; mitochondrial membrane; mitochondrial metabolism; mutant; neutrophil; novel; precursor cell; preservation; prohibitin; protein complex; response

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.

项目摘要/摘要 CLPB基因中的遗传性双重突变是先天性中性粒细胞减少的原因 与Megcann相关，这是一种罕见的常染色体隐性疾病（OMIM条目＃616271）。在它的 严重的形式，该疾病导致死亡几个月，这是由于明显的神经系统而导致的 症状或威胁生命的感染。最近确定了从头单行的突变 CLPB基因以显性阴性的方式起作用，也引起严重的先天性中性粒细胞减少症。 CLPB基因编码含有几种arnkyrin的广泛表达的线粒体蛋白 重复和单个AAA+（与各种细胞活动相关的ATPases）模块。这 CLPB在中性粒细胞前体细胞中功能的分子机制尚不清楚，并且 突变的CLPB变体引起的线粒体缺陷及其与有缺陷的粒状的链接 定义很差。我们假设CLPB对于从糖酵解的代谢转移至关重要 在中性粒细胞分化过程中进行线粒体呼吸。我们将通过 完成两个具体目标。在AIM 1中，我们将确定CLPB在线粒体中的作用 使用粒细胞细胞系模型的形态，代谢和中性粒细胞分化 粒子。这个目标将测试CLPB在 中性粒细胞分化过程中的线粒体重塑和代谢重编程。目标 2，我们将研究疾病突变对CLPB与钥匙之间相互作用的影响 线粒体动力学和CRISTAE形态的调节剂。这个目标将测试子 假设双质突变与单相关突变的作用之间的主要差异 在CLPB活性上是由突变的CLPB变体的不同相互作用倾向引起的。 根据结果​​，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变体的分子缺陷，并将 为开发由CLPB突变引起的中性粒细胞减少症的潜在治疗奠定了基础。