The Nmp4 Anti-Anabolic Bone Axis R01AR070144-01A1

Nmp4 抗合成代谢骨轴 R01AR070144-01A1

• 批准号: 10465066
• 负责人: JOSEPH P BIDWELL
• 金额: $ 42.29万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465066
• 关键词: Address; Adverse effects; Amplifiers; Anabolic Agents; Animals; Apoptosis; Automobile Driving; Biochemical; Biogenesis; Biological Assay; Biological Markers; Bone Marrow; Cells; Chemistry; Collagen; Data; Development; Diffuse; Disease; Effectiveness; Exhibits; Femur; Fracture; Genes; Genetic Translation; Genomics; Goals; Health Care Costs; Intervention; Mechanics; Medical; Mesenchymal; Minerals; Molecular Target; Morbidity - disease rate; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Production; Property; Protein Secretion; Proteins; Publishing; Raloxifene; Resistance; Ribosomes; Role; Secretory Cell; Serum; Signal Pathway; Signal Transduction; Skeleton; Stimulus; Stress Fractures; Testing; Therapeutic Agents; Time; Tissues; Translating; Translations; bone; bone mass; c-myc Genes; cell type; crosslink; endoplasmic reticulum stress; improved; innovation; interest; loss of function mutation; mechanical properties; mineralization; mortality; nanoscale; new therapeutic target; novel; novel therapeutics; osteogenic; osteopontin; osteoprogenitor cell; prevent; response; restoration; side effect; skeletal; stem; stem cells; submicron; therapeutic target; transcription factor; transcriptome; translational potential; treatment response

“The holy grail of osteoporosis therapy remains the restoration of … bone mass…”, and consequent fracture reduction. Current osteoporosis therapies have significant limitations and NIAMS objectives include addressing “why some therapeutic agents become less effective with long-term use and “exploring opportunities for discovery of newly identified molecular targets for new drug treatments”. Mice harboring a loss-of-function mutation in the gene encoding the transcription factor Nmp4 are healthy, long-lived, and exhibit an unremarkable skeletal phenotype until challenged with an anabolic stimulus including several classes of osteoporosis therapies, which elicits enhanced bone formation. The absence of a baseline phenotype, combined with the improved response to therapy, affords a unique advantage for developing Nmp4 (or one of its upstream/downstream components) as a safe target to enhance efficacy of existing therapies and identify molecular targets for new therapies. Our goal is to determine how disabling Nmp4 improves the osteoanabolic response to drug treatments, in order to distinguish targetable molecules that can be translated to patients. Our published and preliminary –omic, biochemical, and bone mechanical data inform our hypothesis that Nmp4 limits the number of osteoprogenitors and regulates the composition, production, and export of the matrix and ultimately bone mechanical properties. Furthermore, loss of Nmp4 in osteogenic cells sharply enhances global mRNA translation, coincident with induction of select portions of the unfolded protein response (UPR), which serve to expand the processing capacity of the ER and facilitate protein secretion, converting the osteoblast into a super-secretory cell. We propose that these super-secretors release a disproportionately high level of osteocalcin and osteopontin that contribute to the formation of fracture resistant bone. Three independent aims will reveal the mechanisms underlying Nmp4 action. Aim #1: identify the specific cell type(s) driving the Nmp4-/- response to anabolic agents. Ovariectomized mice harboring selective genomic deletion (flox) of Nmp4 from MSPCs, osteoblasts, or osteoclasts will be treated with mono- and combination osteoporosis therapies. To target the Nmp4 pathways for pharmacological intervention it is crucial to identify the cell type driving the beneficial effects. Aim #2: determine how Nmp4 regulates osteoblast ribosome biogenesis, global and gene-specific mRNA translation rates of matrix proteins, and strategic portions of the UPR coincident with control of ER expansion. The UPR pathway is a potential therapeutic target for numerous disorders including osteoporosis. Aim #3: determine the matrix and mineral composition of the Nmp4-/- bone in the context of energy dissipation mechanisms subsequent to fatigue and fracture toughness tests. Completion of this aim will provide perspectives into the relationship between the osteoblast secretome and bone material properties. We have a powerful way to magnify the effectiveness of existing osteoporosis therapies and provide novel molecular targets for new therapies.

“骨质疏松疗法的圣杯仍然是……骨骼质量的恢复……” 电流。 解决“为什么某些治疗剂在长期使用和“探索”中的效果降低 发现新药物治疗的新鉴定的分子靶标的机会”。 编码转录因子NMP4基因的功能丧失突变是健康的，长寿的，并且 表现出不明显的骨骼表型，直到被合成代谢刺激挑战，包括几个 骨质疏松疗法的类别，引起了骨的形成。 表型结合了对治疗的改进反应，为开发NMP4提供了独特的优势 （或它的上游/下游组件之一）作为增强现有疗法和的安全目标 确定新疗法的分子靶标。 为了区分可以翻译的可靶向分子，骨食品代谢对药物治疗的反应 给患者。 NMP4限制了骨基因生成剂的数量并调节组成，生产和 进出基质和最终的骨骼机械性能。 急剧增强了全球mRNA翻译，同时又归因于公正的某些部分。 蛋白质反应（UPR），可扩大ER的加工胶囊并促进蛋白质 分泌，将成骨细胞转换为超级分泌细胞 释放出高度高的骨钙素和骨桥蛋白，有助于形成 抗断裂的骨骼。 AIM＃1：确定驱动NMP4 - / - 对合成代谢剂的响应的特定细胞类型。 将处理MSPC，成骨细胞或破骨细胞的NMP4的选择性基因组缺失（FLOX） 用骨质疏松症组合疗法。 间隔至关重要的是要确定推动福利的十二级。 调节成骨细胞核糖体生物发生，基因和基因特异性mRNA翻译速率，基质蛋白， UPR的战略部分与膨胀路径的控制相吻合。 包括骨质疏松症在内的许多疾病的治疗靶标。 NMP4 - / - 骨的矿物质成分在耗能耗散机制的背景下 疲劳和果实测试。 在成骨细胞的分泌材料和骨骼材料特性之间。 现有的骨质疏松疗法的有效性，并为新疗法提供新的分子靶标。

项目成果

NMP4 regulates the innate immune response to influenza A virus infection.

NMP4 调节对甲型流感病毒感染的先天免疫反应。

• DOI: 10.1038/s41385-020-0280-z
• 发表时间: 2021
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Yang,Shuangshuang;Adaway,Michele;Du,Jianguang;Huang,Shengping;Sun,Jie;Bidwell,JosephP;Zhou,Baohua
• 通讯作者: Zhou,Baohua