Multivalent Presentation of Growth Factors Regulates Cellular Responses

数以百万计的美国人和世界各地的人因受伤、骨缺陷、 和脊柱缺陷，因此非常需要有效的治疗来再生骨骼 并促进骨骼生长。在现代医学正在探索的治疗方法中， 服用促进我们身体再生骨骼的生长因子代表着一种 有吸引力的方向，因为它的非侵入性和利用我们自己的细胞，包括骨 形成干细胞。这种使用骨生长因子的治疗方法已被FDA批准。 并成功地用于临床，然而这种治疗的一个公认的缺点是 服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 对某些患者的影响。我们的团队认为目前的高剂量是没有必要的，如果有更好的 将生长因子呈现给细胞的策略，例如，将5个生长因子绑定在一起作为明确定义的 聚集的生长因子分子与1000个单独的生长因子分子在细胞周围游动。有了这个 研究，我们希望开发出比目前更有效的方式来呈现增长因素 大剂量注射途径。我们的方法是受到自然本身的启发 “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蜂窝响应。这项建议的基础是 我们的发现是，COMP，一种最初从软骨中分离出来的蛋白质，可以与多种骨骼结合 所有的增长因素都会同时出现。我们计划研究COMP如何与增长因素绑定，有多少 每个Comp可以携带的增长因素(1到10)，以及哪种情况最适合 骨骼再生。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来向干细胞提供生长因子，细胞对其做出反应 极大地增强了活动，包括健壮的骨骼形成和生长。结果来自于 这项研究将极大地增强我们目前对骨生长因子如何 在细胞水平上调节骨形成，使我们更接近非侵入性和 干细胞为基础的骨再生疗法。

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.