Role of NHA-oc/NHA2 in Osteoclast Differentiation and Function

NHA-oc/NHA2 在破骨细胞分化和功能中的作用

• 批准号: 7990883
• 负责人: Ricardo Anibal Battaglino
• 金额: $ 22.25万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990883
• 关键词: Affect; Albers-Schonberg disease; Amino Acids; Apoptosis; Bacteria; Bone Development; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone Resorption; Candidate Disease Gene; Carbonic Anhydrase II; Cations; Cell Volumes; Cells; Cessation of life; Charge; Chloride Channels; Deformity; Dimerization; Disease; Equilibrium; Essential Amino Acids; Eukaryota; Evolution; Excision; Failure; Future; Gene Family; Generations; Genes; Goals; Hand; Health; Hereditary Disease; Homologous Gene; Human; Human Development; In Vitro; Ion Transport; Knowledge; Lead; Macrophage Colony-Stimulating Factor; Maintenance; Malignant - descriptor; Mammalian Cell; Mitochondria; Modeling; Molecular; Mus; Mutation; Names; Osteoclasts; Osteolytic; Osteoporosis; Padan; Pattern; Pharmaceutical Preparations; Phenotype; Plasmids; Play; Prevention; Proteins; Proton Pump; Protons; Regulation; Role; Saccharomyces cerevisiae; Single Nucleotide Polymorphism; Sodium; Sodium Chloride; Sodium-Hydrogen Antiporter; Structure; System; TNFSF11 gene; Testing; Therapeutic Intervention; Western Blotting; Work; Yeast Model System; Yeasts; antiport; antiporter; base; bone; bone loss; bone mass; design; disorder control; in vivo; innovation; monocyte; mutant; novel; particle; protein expression; public health relevance; selective expression; sodium-translocating ATPase

DESCRIPTION (provided by applicant): Bone resorption by osteoclasts is essential for normal bone development. Osteoclast deficiency leads to osteopetrosis, which is characterized by increased bone mass and may lead to bone deformities or in severe cases, to death. Increased numbers and activity of osteoclasts, on the other hand, cause increased bone resorption, and may lead to osteoporosis and other osteolytic diseases. A better understanding of the molecular regulation of osteoclast formation, activity, and survival will provide novel targets for therapeutic intervention in the control of these diseases. We recently identified and cloned a gene, NHAoc/NHA2, that encodes a novel Na+/H+ antiporter that is the first mitochondrial NHA characterized to date. NHAoc/NHA2 is highly and selectively expressed in osteoclasts and displays the expected ion transport activities of a bona fide NHA. We have demonstrated that this gene plays a role(s) in normal osteoclast differentiation, apoptosis and bone resorptive function in vitro. Extensive mutational analysis of a bacterial homologue, NhaA, has revealed a number of amino acid residues essential for its activity. Some of these residues are evolutionarily conserved and have been shown to be essential not only for activity of NhaA in bacteria, but also of NHAoc in eukaryotes. We hypothesize that evolutionarily conserved amino acids that are essential for NhaA antiporter activity, pH regulation and dimerization will have a similar role in NHAoc/NHA2 and that mutations in those amino acid residues will impact NHAoc activity and therefore osteoclast function in vitro and in vivo. PUBLIC HEALTH RELEVANCE: Osteoclasts are cells that are responsible for bone removal ('resorption') during normal bone development and maintenance. Abnormal osteoclast numbers and/or activity, on the other hand, can cause a spectrum of diseases ranging from osteopetrosis to osteoporosis. This project seeks to determine the role of a novel gene that we have discovered in osteoclasts, termed 'NHA-oc/NHA2', in regulating bone mass. This work will aid us in the design of appropriate new therapies based on drugs that interfere with NHA-oc/NHA2 activity for the prevention of pathological bone loss.

描述（由申请人提供）：破骨细胞的骨吸收对于正常的骨骼发育至关重要。破骨细胞缺乏会导致骨质造成病，其特征是骨骼量增加，可能导致骨畸形或在严重的情况下死亡。另一方面，破骨细胞的数量和活性增加会导致骨吸收增加，并可能导致骨质疏松症和其他骨质疾病。更好地了解破骨细胞形成，活性和生存的分子调节将为控制这些疾病的治疗干预提供新的靶标。 我们最近确定并克隆了一个基因Nhaoc/nha2，该基因编码了一种新型的Na+/H+抗植物，这是迄今为止的第一个线粒体NHA。 NHAOC/NHA2在破骨细胞中高度有选择地表达，并显示真正的NHA的预期离子运输活动。我们已经证明，该基因在体外的正常破骨细胞分化，凋亡和骨吸收功能中起作用。 对细菌同源物NHAA的广泛突变分析揭示了许多对其活性必不可少的氨基酸残基。其中一些残基在进化上是保守的，并且已被证明是细菌中NHAA的活性至关重要的，而且对真核生物中的NHAOC也是必不可少的。 我们假设在NHAA抗毒剂活性，pH调节和二聚化的进化保守氨基酸中将在NHAOC/NHA2中具有相似的作用，并且这些氨基酸残基中的突变会影响NHAOC活性，从而影响NHAOC的活性，从而影响骨细胞在体内和VIVO中的骨质骨化功能。 公共卫生相关性：破骨细胞是在正常骨骼发育和维持过程中负责去除骨骼（“吸收”）的细胞。另一方面，异常的破骨细胞数量和/或活性可能会导致从骨质疏松症到骨质疏松症的各种疾病。该项目旨在确定我们在调节骨骼质量中发现的新型基因的作用，称为“ NHA-OC/NHA2”。这项工作将帮助我们设计基于干扰NHA-OC/NHA2活性的药物来设计适当的新疗法，以预防病理骨质流失。