Functional Analysis of NHA-oc/NHA2 in vivo

NHA-oc/NHA2体内功能分析

• 批准号: 7659289
• 负责人: Ricardo Anibal Battaglino
• 金额: $ 10.18万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659289
• 关键词: Albers-Schonberg disease; Animals; Apoptosis; Bone Density; Bone Development; Bone Diseases; Bone Marrow Cells; Bone Resorption; Candidate Disease Gene; Cations; Cells; Cessation of life; Data; Deformity; Disease; Excision; Exhibits; Functional disorder; Gene Deletion; Genes; Genetic Transcription; Goals; Hand; Homeostasis; Human; Human Development; In Vitro; Innate Bone Remodeling; Intervention; Ion Transport; Knockout Mice; Lead; Maintenance; Mediating; Metabolic Bone Diseases; Mitochondria; Mitochondrial Swelling; Molecular; Mus; Mutant Strains Mice; Osteoclasts; Osteolytic; Osteoporosis; Ovariectomy; Paget' s Disease; Pathway interactions; Pharmaceutical Preparations; Play; Prevention; Prevention approach; Process; Proteins; Proton Pump; Protons; RNA; RNA Interference; Regulation; Reporting; Residual state; Role; Sodium-Hydrogen Antiporter; Testing; Therapeutic Intervention; Wild Type Mouse; Work; antiport; antiporter; base; bone; bone loss; bone mass; design; disorder control; in vivo; innovation; insight; mouse model; novel; novel strategies; public health relevance; selective expression; skeletal disorder

DESCRIPTION (provided by applicant): Bone destruction 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. Recently, we identified a gene, nha-oc/NHA2, which is strongly up-regulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation/proton antiporter (CPA) that is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na+dependent mitochondrial swelling. NHA-oc/NHA2 is therefore the first characterized mammalian mitochondrial CPA2. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and bone resorption, strongly indicating a role for NHA-oc/NHA2 in these processes. In Aim 1, we will characterize the role of NHA-oc/NHA2 in bone homeostasis in vivo by using a knockout mouse model carrying a mutagenic retroviral insertion in the nha-oc/NHA2 locus. In Aim 2, we will characterize the role of NHA-oc/NHA2 on pathological bone loss in vivo. For that, we will compare bone loss induced by ovariectomy in wild type and homozygous mutant mice. The effects of nha-oc/NHA2 on osteoclast formation and bone resorption in vivo will be determined using a variety of analytic approaches for bone. Our goal is to establish the role that NHA-oc/NHA2 plays in osteoclast differentiation and function, and ultimately in regulating bone mass in vivo. These studies may identify a new candidate gene involved in the development of human osteopetrosis as well as provide an important new target for anti-resorptive therapies. PUBLIC HEALTH RELEVANCE: Osteoclasts are cells that are responsible for bone removal ('resorption') during normal bone development and maintenance. In contrast, abnormal osteoclast numbers and/or activity 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 osteoclast formation, function and ultimately in regulating bone mass in vivo. 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）：破骨细胞破坏骨骼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。最近，我们鉴定了一个基因NHA-OC/NHA2，该基因在RANKL诱导的破骨细胞分化的体外和体内被强烈上调。 NHA-OC/NHA2编码在破骨细胞中选择性表达的新型阳离子/质子抗植物（CPA）。 NHA-OC/NHA2蛋白定位于线粒体，在该线粒体中介导Na+依赖性线粒体肿胀。因此，NHA-OC/NHA2是第一个表征的哺乳动物线粒体CPA2。 NHA-OC/NHA2的RNA沉默可减少破骨细胞的分化和骨吸收，强烈表明NHA-OC/NHA2在这些过程中的作用。在AIM 1中，我们将通过使用在NHA-OC/NHA2基因座中携带诱变性逆转录病毒插入的基因敲除小鼠模型来表征NHA-OC/NHA2在体内骨体内平衡中的作用。在AIM 2中，我们将表征NHA-OC/NHA2在体内病理骨质流失方面的作用。为此，我们将比较野生型和纯合突变小鼠卵巢切除术引起的骨质流失。 NHA-OC/NHA2对体内破骨细胞形成和骨吸收的影响将使用多种骨骼的分析方法确定。我们的目标是确定NHA-OC/NHA2在破骨细胞分化和功能中发挥作用的作用，并最终在调节体内骨骼质量方面。这些研究可能会发现与人类骨质造成病的发展有关的新候选基因，并为抗敏感性疗法提供了重要的新靶标。 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。相比之下，异常的破骨细胞数量和/或活性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破骨细胞中发现的一种新型基因的作用，称为“ Nha-oc/nha2”，在破骨细胞形成，功能和最终在体内调节骨骼质量方面的作用。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。