Systematic Design of Biomimetic Basement Membranes

描述(由申请人提供)：该提案采用仿生方法来了解生物材料的组成和结构如何与接触的细胞所经历的机械和整合素结合部位环境相关，然后改变这些参数以获得所需的细胞行为。由于基底膜在体内具有广泛的相关性(例如，作为牙龈上皮细胞的底物)，仿生基底膜将被开发出来。利用细胞固体模型和粘弹性理论预测IV型胶原/层粘连蛋白双组分材料的弹性系数，以及通过计算整合素键数从分子组成预测细胞黏附强度的假设将受到考验。第二个假设是，通过改变膜的层粘连蛋白/IV型胶原的组成，可以在保持整合素键数不变的同时改变膜的弹性模数，反之亦然。其具体目的是组装和表征IV型胶原或层粘连蛋白的单组分膜，通过共组装IV型胶原和层粘连蛋白来组装和表征双组分膜，最后系统地改变机械弹性系数和整合素结合部位的密度，以实现细胞迁移行为的差异。潜在的应用范围从牙科植入物的涂层到人造血管移植物。尤其是在牙科应用中，生物活性材料将能够加强牙龈上皮衬里与种植体的结合，以排除上皮下牙龈组织中的细菌。这位候选人在麻省理工学院的道格拉斯·劳芬伯格博士和罗杰·卡姆博士的实验室获得了博士学位，并在自组装生物材料领域积累了专业知识，这些材料可能会用于医疗植入物。目前杜克大学哈罗德·埃里克森博士实验室的博士后研究将候选人的知识扩展到自然产生的细胞外基质蛋白的自组装中。在接受了亚利桑那州立大学助理教授的职位后，这位候选人的直接目标是为他的实验室的学习环境和生产力奠定坚实的基础。从长远来看，这项研究将协同结合候选人在生物材料合理设计和细胞外基质自组装方面的专业知识来生产生物活性材料。

DESCRIPTION (provided by applicant): This proposal takes a biomimetic approach to understanding how biomaterial composition and structure relate to the mechanical and integrin binding site environment experienced by contacted cells and then varies these parameters to elicit desired cell behaviors. Since basement membranes have wide relevance in the body (e.g., as a substrate for gingival epithelial cells), biomimetic basement membranes will be developed. The hypothesis that the elastic modulus of two-component collagen IV/laminin materials can be predicted from their molecular composition using the cellular solids model and visco-elastic theory and that their cell adhesion strength can be predicted from molecular composition through calculating the number of integrin bonds will be tested. A second hypothesis that it is possible to vary the membrane elastic modulus while holding the integrin bond number constant and vice versa, by variation of the laminin/collagen IV composition of the membrane, will also be tested. The Specific Aims are to assemble and characterize single-component membranes of collagen IV or laminin, assemble and characterize two-component membranes by co-assembling collagen IV and laminin, and finally systematically vary the mechanical modulus and integrin binding site density to achieve differences in cell migration behavior. Potential applications range from coatings for dental implants to artificial vascular grafts. In particular for dental applications, a bioactive material would be able to strengthen binding of the epithelial lining of the gingiva to the implant in order to exclude bacteria from the subepithelial gingival tissue. The candidate, having completed a PhD in the laboratories of Dr. Douglas Lauffenburger and Dr. Roger Kamm at MIT, has developed expertise in the field of self-assembling biomaterials that have potential use in medical implants. Current post-doctoral research in the laboratory of Dr. Harold Erickson at Duke University extends the candidate's knowledge into the self-assembly of naturally occurring extracellular matrix proteins. Having accepted a position as Assistant Professor at Arizona State University, the candidate's immediate goal is to lay a strong foundation for the learning environment and productivity of his laboratory. In the long term, this research will synergistically combine the candidate's expertise in the rational design of biomaterials and extracellular matrix self-assembly to produce bioactive materials.