Multivalent Presentation of Growth Factors Regulates Cellular Responses

生长因子的多价呈现调节细胞反应

• 批准号: 9312194
• 负责人: Dominik R Haudenschild
• 金额: $ 31.76万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312194
• 关键词: Actins; Adverse effects; Affect; American; Animal Model; Atomic Force Microscopy; BMP2 gene; Binding; Binding Proteins; Binding Sites; Biochemistry; Biology; Bone Diseases; Bone Growth; Bone Morphogenetic Protein 10; Bone Morphogenetic Proteins; Bone Regeneration; Buffers; Cartilage; Cartilage Matrix; Cell Communication; Cell Therapy; Cells; Clinic; Clinical; Collaborations; Collagen; Data; Defect; Dose; Engineering; Environment; Extracellular Matrix; FDA approved; Formulation; Fracture; Gene Expression; Generic Drugs; Glues; Goals; Growth Factor; Homeostasis; Homo; Imaging Device; In Vitro; Individual; Injectable; Injury; Investigation; Knowledge; MAPK14 gene; Mediating; Membrane; Modeling; Modern Medicine; Molecular; Molecular Models; Nanotechnology; Natural regeneration; Nature; Osteogenesis; Patients; Peptide antibodies; Physiologic Ossification; Physiological; Pre-Clinical Model; Process; Protein Binding Domain; Proteins; Proteoglycan; Rattus; Recruitment Activity; Research; Research Personnel; Resolution; Signal Transduction; Site-Directed Mutagenesis; Solid; Spinal; Spinal Fusion; Stem cells; Structure; Surgeon; Swimming; Testing; Time; Translating; Transmission Electron Microscopy; Validation; Work; base; bioimaging; bone; bone engineering; bone growth factor; bone morphogenetic protein receptors; clinically relevant; design; dosage; effective therapy; high resolution imaging; improved; in vivo; in vivo Model; insight; interdisciplinary approach; macromolecular assembly; mammalian COMP; microscopic imaging; molecular modeling; monomer; neutralizing antibody; novel strategies; osteogenic; osteogenic protein; pre-clinical; protein complex; protein function; receptor; reconstitution; repaired; response; rho; stem cell differentiation

Millions of Americans and people worldwide suffer bone diseases due to injuries, bone defects, and spinal defects, and therefore are in great need of effective treatments to regenerate bone and promote bone growth. Among treatments being explored in modern medicine, administration of growth factors that prompt our own body to regrow bone represents an attractive direction due to its non-invasiveness and utilization of our own cells, including bone- forming stem cells. Such treatment with bone growth factors has been approved by the FDA and is successfully used in clinics, however a recognized drawback of this treatment is that the administration of extremely high doses of very pure growth factor inevitably causes severe side effects in some patients. Our team believes current high doses are not necessary, with better tactics to present growth factors to cells, e.g. 5 growth factors bound together as a well-defined cluster versus 1000 individual growth factor molecules swimming around the cells. With this research, we hope to develop more effective ways to present growth factors than the current approach of injecting high dosage. Our approach is inspired by the way nature itself ‘administers’ these growth factors, which is always in combination with other proteins that provide the necessary context and help fine-tune cellular responses. This proposal builds on our discovery that COMP, a protein originally isolated from cartilage, can bind to multiple bone growth factors all at once. We plan to study how the COMP binds to growth factors, how many growth factors each COMP can carry (1 to 10), and which of the situations work best towards bone regeneration. We believe our results shall demonstrate that this multi-valent binding provides a new platform to present the growth factors to stem cells, to which cells respond with dramatically enhanced activities including robust bone formation and growth. The results from this investigation shall greatly enhance our current understanding of how bone growth factors regulate bone formation at the cellular level, and bring us a giant step closer to non-invasive and stem cell based therapy for bone regeneration.

由于受伤，骨骼缺陷，全球数百万的美国人和人都患有骨骼疾病 和脊柱缺陷，因此非常需要有效治疗以再生骨骼 并促进骨骼生长。在现代医学中探索的治疗方法中， 促使我们自己身体改革骨骼的增长因素的管理代表 有吸引力的方向，由于其无创性和我们自己细胞的利用，包括骨骼 形成干细胞。通过FDA批准了使用骨骼生长因子的这种治疗 并且成功地用于诊所，但是这种治疗方法的公认缺点是 给药极高的非常纯的生长因子不可避免地会导致严重的一面 对某些患者的影响。我们的团队认为目前的高剂量不是必需的，更好 将生长因子呈现给细胞的策略，例如5个增长因素作为一个定义明确的 簇与1000个单个生长因子分子在细胞周围游泳。与此 研究，我们希望开发出比当前的更有效的方法来提出增长因素 注射高剂量的方法。我们的方法受到自然本身的方式的启发 “管理”这些增长因素，这些因素始终与其他蛋白质结合 提供必要的上下文并帮助微调蜂窝响应。该提议建立在 我们的发现，Comp是一种最初与软骨分离的蛋白质，可以与多个骨头结合 生长因素一次。我们计划研究Comp如何与生长因子结合，多少 每个补偿都可以携带的增长因素（1至10），哪些情况最适合 骨再生。我们认为我们的结果将表明这种多价约束力 提供了一个新的平台，以呈现干细胞的生长因素，并以此对细胞响应 龙增强的活动，包括稳健的骨骼形成和生长。结果 这项投资将大大增强我们对骨骼生长如何如何的当前理解 调节细胞水平的骨形成，使我们更接近无创和 基于干细胞的骨骼再生治疗。