Schnurri-3 Inhibitors: specific inducers of adult bone formation

Schnurri-3 抑制剂：成人骨形成的特异性诱导剂

• 批准号: 8259713
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 4.04万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-21 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259713
• 关键词: 3' Untranslated Regions; Address; Adult; Adverse effects; Affect; Age; Aging; Alkaline Phosphatase; Biological; Biological Assay; Biological Preservation; Bone Resorption; Cell Line; Cells; Characteristics; Chemicals; Deposition; Disease; Disease Progression; Dose; Drug Delivery Systems; Environment; Equilibrium; Family; Fireflies; Firefly Luciferases; Fracture; Gene Expression; Generations; Genes; Goals; Health; Hematopoiesis; Human; In Vitro; Incidence; Individual; Inhibitory Concentration 50; Institutes; Large T Antigen; Libraries; Luc Gene; Maintenance; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Messenger RNA; Morbidity - disease rate; Morphogenesis; Morphology; Mus; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pharmaceutical Preparations; Phenotype; Physiological; Population; Prevention; Process; Property; Proteins; Refractory; Renilla Luciferases; Reporter; Series; Simian virus 40; Skeletal system; Skeleton; Source; Specificity; Technology; Testing; Therapeutic; Transcript; United States; Untranslated Regions; Zinc Fingers; base; bone; bone loss; bone mass; cost; cytotoxic; design; high throughput screening; in vivo; inhibitor/antagonist; interest; member; mineralization; mortality; novel; null mutation; osteoblast differentiation; osteogenic; postnatal; prevent; promoter; public health relevance; response; skeletal; skeletal disorder; small hairpin RNA; small molecule; therapeutic target

DESCRIPTION (provided by applicant): In a normal physiological state the skeletal system provides mobility, protection for vital organs and serves as an essential environment in which hematopoiesis can occur [1]. To achieve these functions, the skeleton exists in a dynamic equilibrium characterized by continuous osteoclast-mediated resorption of bone and osteoblast- mediated bone deposition [2]. Maintenance of this homeostatic remodeling is disrupted during aging leading to debilitating bone loss referred to as osteoporosis that affects over 10 million individuals in the United States [3]. As an individual ages, the progression of this disease results in an increased incidence of fracture that results in serious health consequences [4]. Since few therapeutic options are available for the prevention or treatment of osteoporosis, our goal is to develop novel mechanism-based treatments that increase anabolic bone formation and prevent bone loss. We have recently identified Schnurri-3 (Shn3), a member of the Schnurri family of large zinc-finger proteins, as an essential regulator of adult bone formation [5]. Our generation and subsequent analysis of mice bearing a null mutation in Shn3 (Shn3-/- mice) revealed a profound high-bone mass phenotype that arises through augmented osteoblast activity and is characterized by greatly increased rates of bone formation. The osteosclerotic phenotype observed in Shn3-/- mice does not affect skeletal morphology since its onset is postnatal. However, the loss of Shn3 renders these mice refractory to the age-associated loss in bone that occurs in control mice. The characteristics of Shn3-/- bone: increased bone anabolic activity, preservation of normal morphogenesis, mineralization and biophysical properties suggest that this protein is an ideal therapeutic target for the treatment of certain skeletal disorders. Unfortunately, structural analysis of Shn3 has revealed a dearth of functional domains within this protein that are suitable for drug targeting. We have, however, demonstrated that shRNA targeting of the 3'UTR of Shn3 reduces protein levels and augments osteoblast function in vitro. Furthermore, we have determined that post-transcriptional blockade of Shn3 results in increased bone mass in vivo. Therefore, we have designed a series of cell-based assays that will allow for the identification of chemical probes that selectively reduce Shn3 protein levels through a post- transcriptional mechanism targeting the 3'UTR of this gene. The identification of compounds that decrease Shn3 levels would provide a valuable therapeutic approach to prevent the destructive bone loss associated with osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis is a debilitating disease of the skeletal system that currently affects over 10 million individuals in the United States. Disease progression results in an increased incidence of fracture that results in serious health consequences and will present an expanding source of morbidity and mortality in an aging global population. While a few classes of medications are available to either prevent bone loss or increase bone formation in the setting of osteoporosis or cancer, current therapeutics are far from ideal due to toxic side effects, intolerance, or prohibitive cost. The ultimate goal of this proposal is to develop mechanism-based treatments to prevent bone loss and to increase anabolic bone formation. 2

描述(申请人提供)：在正常的生理状态下，骨骼系统为重要器官提供活动和保护，是发生造血的基本环境[1]。为了实现这些功能，骨骼处于动态平衡中，其特征是持续的破骨细胞介导的骨吸收和成骨细胞介导的骨沉积[2]。这种动态平衡重塑的维持在衰老过程中被破坏，导致被称为骨质疏松症的衰弱性骨丢失，在美国有1000多万人受到影响[3]。随着个人年龄的增长，这种疾病的发展会导致骨折发生率的增加，从而导致严重的健康后果[4]。由于预防或治疗骨质疏松症的治疗方案很少，我们的目标是开发新的基于机制的治疗方法，增加合成代谢骨的形成，防止骨丢失。我们最近发现SchNurri-3(Shn3)是SchNurri大锌指蛋白家族的成员，是成人骨形成的重要调节因子[5]。我们这一代和随后对携带Shn3零突变的小鼠(Shn3-/-小鼠)的分析揭示了一种深刻的高骨量表型，这种表型是通过增强成骨细胞活性而产生的，其特征是骨形成率大大增加。在Shn3-/-小鼠中观察到的骨硬化性表型不会影响骨骼形态，因为它是在出生后发病的。然而，Shn3的丢失使这些小鼠不能像对照组小鼠那样，出现与年龄相关的骨质丢失。Shn3-/-bone的特点：骨合成活性增强，保持了正常的形态发生、矿化和生物物理性质，这表明该蛋白是治疗某些骨骼疾病的理想靶点。不幸的是，对Shn3的结构分析表明，该蛋白中缺乏适合于药物靶向的功能结构域。然而，我们已经证明，靶向Shn3的3‘UTR的shRNA在体外降低了蛋白水平并增强了成骨细胞的功能。此外，我们已经确定转录后阻断Shn3会导致体内骨量增加。因此，我们设计了一系列基于细胞的分析方法，以识别通过针对Shn3基因的3‘UTR的转录后机制选择性降低Shn3蛋白水平的化学探针。识别降低Shn3水平的化合物将为预防与骨质疏松相关的破坏性骨丢失提供一种有价值的治疗方法。 公共卫生相关性：骨质疏松症是一种使骨骼系统衰弱的疾病，目前在美国影响着1000多万人。疾病进展导致骨折发生率增加，从而导致严重的健康后果，并将在老龄化的全球人口中成为发病率和死亡率的不断扩大的来源。虽然在骨质疏松症或癌症的情况下，有几种药物可以防止骨丢失或增加骨形成，但由于毒副作用、不耐受性或高昂的成本，目前的治疗方法远不理想。这项建议的最终目标是开发基于机制的治疗方法，以防止骨丢失和增加合成代谢骨的形成。2.