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.

“骨质疏松症治疗的圣杯仍然是恢复……骨量……”以及随之而来的骨折 减少。目前的骨质疏松症治疗有很大的局限性，NIAMS 的目标包括 解决“为什么某些治疗药物长期使用后效果会降低”以及“探索 发现新确定的新药物治疗分子靶点的机会”。携带 编码转录因子 Nmp4 的基因发生功能丧失突变是健康、长寿和 在受到合成代谢刺激（包括多种刺激）的挑战之前，表现出不起眼的骨骼表型 骨质疏松症治疗的类别，可促进骨形成。缺乏基线 表型与治疗反应的改善相结合，为开发 Nmp4 提供了独特的优势 （或其上游/下游成分之一）作为增强现有疗法疗效的安全目标， 确定新疗法的分子靶点。我们的目标是确定禁用 Nmp4 如何改善 对药物治疗的骨合成代谢反应，以区分可转化的靶向分子 给患者。我们已发表的初步组学、生化和骨力学数据为我们提供了信息 假设 Nmp4 限制骨祖细胞的数量并调节其组成、产生和代谢 输出基质和最终的骨机械特性。此外，成骨细胞中 Nmp4 的缺失 急剧增强整体 mRNA 翻译，与诱导未折叠的选定部分同时发生 蛋白质反应（UPR），其作用是扩大内质网的处理能力并促进蛋白质 分泌，将成骨细胞转化为超分泌细胞。我们建议这些超级秘书 释放不成比例的高水平骨钙素和骨桥蛋白，有助于形成 抗骨折骨。三个独立的目标将揭示 Nmp4 作用的机制。 目标#1：确定驱动 Nmp4-/- 对合成代谢药物做出反应的特定细胞类型。卵巢切除小鼠 MSPC、成骨细胞或破骨细胞中含有 Nmp4 选择性基因组缺失 (flox) 的患者将接受治疗 骨质疏松症的单一和联合疗法。靶向 Nmp4 途径进行药理学 干预中，确定产生有益效果的细胞类型至关重要。目标#2：确定 Nmp4 如何 调节成骨细胞核糖体生物发生、基质蛋白的整体和基因特异性 mRNA 翻译率， UPR 的战略部分与 ER 扩张的控制一致。 UPR途径是一个潜在的途径 包括骨质疏松症在内的许多疾病的治疗目标。目标#3：确定矩阵并 Nmp4-/-骨在能量耗散机制背景下的矿物成分 疲劳和断裂韧性测试。完成这一目标将为双方关系提供视角 成骨细胞分泌组和骨材料特性之间的关系。我们有一个强大的方法来放大 现有骨质疏松症治疗的有效性，并为新疗法提供新的分子靶点。

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