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.

数以百万计的美国人和全世界的人由于受伤、骨缺损、 和脊柱缺损，因此非常需要有效的治疗方法来再生骨骼。 促进骨骼生长在现代医学正在探索的治疗方法中， 给予生长因子，促使我们自己的身体再生骨骼， 有吸引力的方向，由于其非侵入性和利用我们自己的细胞，包括骨- 形成干细胞这种用骨生长因子治疗的方法已经被FDA批准 并成功地用于临床，然而，这种治疗的公认缺点是， 施用极高剂量的非常纯的生长因子不可避免地引起严重的副作用， 对一些患者的影响。我们的团队认为，目前的高剂量是没有必要的， 将生长因子呈递给细胞的策略，例如5种生长因子结合在一起作为一种明确的 相对于1000个单独的生长因子分子在细胞周围游动。与此 研究，我们希望开发出比目前更有效的方法来呈现生长因子 注射高剂量的方法。我们的方法受到自然本身的启发 “管理”这些生长因子，它总是与其他蛋白质结合， 提供必要的环境并帮助微调细胞反应。该提案基于 我们发现COMP是一种最初从软骨中分离出来的蛋白质， 所有的生长因子都在一次。我们计划研究COMP如何与生长因子结合， 每个COMP可以携带的生长因子（1到10），以及哪种情况最适合 骨再生我们相信我们的结果将证明这种多价结合 提供了一个新的平台，将生长因子呈递给干细胞，细胞对此做出反应， 显著增强的活动，包括强健的骨形成和生长。的结果 这项研究将大大提高我们目前对骨生长因子 在细胞水平上调节骨形成，使我们向非侵入性和 干细胞治疗骨再生