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: 8109218
• 负责人: Ricardo Anibal Battaglino
• 金额: $ 25.59万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109218
• 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; 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; 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骨发育至关重要。破骨细胞缺乏导致骨硬化症，其特征是骨量增加，并可能导致骨畸形或在严重情况下导致死亡。另一方面，破骨细胞数量和活性的增加导致骨吸收增加，并可能导致骨质疏松症和其他溶骨性疾病。更好地了解破骨细胞形成、活性和存活的分子调控将为控制这些疾病的治疗干预提供新的靶点。 我们最近确定并克隆了一个基因，NHAoc/NHA 2，编码一种新的Na+/H+反向转运蛋白，这是迄今为止第一个线粒体NHA的特点。NHAoc/NHA 2在破骨细胞中高度选择性表达，并显示出真正NHA的预期离子转运活性。我们已经证明该基因在体外正常破骨细胞分化、凋亡和骨吸收功能中起作用。 对细菌同系物NhaA的广泛突变分析揭示了其活性所必需的许多氨基酸残基。这些残基中的一些在进化上是保守的，并且已被证明不仅对于细菌中的NhaA的活性是必需的，而且对于真核生物中的NHAoc也是必需的。 我们假设，进化上保守的氨基酸，NhaA反向转运蛋白的活性，pH调节和二聚体将在NHAoc/NHA 2中具有类似的作用，这些氨基酸残基的突变将影响NHAoc活性，因此在体外和体内破骨细胞的功能。 公共卫生相关性：破骨细胞是在正常骨发育和维持过程中负责骨去除（“再吸收”）的细胞。另一方面，破骨细胞数量和/或活性异常可引起从骨硬化症到骨质疏松症的一系列疾病。该项目旨在确定我们在破骨细胞中发现的一种新基因（称为“NHA-oc/NHA 2”）在调节骨量中的作用。这项工作将帮助我们设计基于干扰NHA-a/NHA 2活性的药物的适当的新疗法，以预防病理性骨丢失。