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世界各地的人们因受伤、骨缺陷、 和脊柱缺陷，因此非常需要有效的治疗方法来再生骨骼 在现代医学正在探索的治疗方法中， 施用促进我们自己的身体再生骨骼的生长因子代表了一种 由于其非侵入性和利用我们自己的细胞（包括骨细胞），这是一个有吸引力的方向 这种用骨生长因子形成干细胞的治疗已获得 FDA 批准。 并已成功应用于临床，然而，这种治疗方法的一个公认的缺点是 施用极高剂量的非常纯的生长因子不可避免地会导致严重的副作用 我们的团队认为目前的高剂量没有必要，用更好的剂量。 向细胞呈现生长因子的策略，例如 5 个生长因子结合在一起作为明确定义的 集群与 1000 个单独的生长因子分子在细胞周围游动。 研究中，我们希望开发出比目前更有效的方式来呈现生长因子 我们的方法受到大自然本身方式的启发。 “管理”这些生长因子，它们总是与其他蛋白质结合在一起 提供必要的背景并帮助微调细胞反应。 我们发现 COMP（一种最初从软骨中分离出来的蛋白质）可以与多个骨骼结合 我们计划研究COMP如何与生长因子结合，有多少。 每个COMP可以携带的生长因子（1到10），以及哪种情况最适合 我们相信我们的结果将证明这种多价结合。 提供了一个将生长因子呈现给干细胞的新平台，细胞对此做出反应 显着增强活动，包括强健的骨骼形成和生长。 这项研究将极大地增强我们目前对骨生长因子如何发挥作用的理解 在细胞水平上调节骨形成，使我们离非侵入性和非侵入性又近了一大步 基于干细胞的骨再生疗法。