Utilization of Collagen Remodeling Pathways to Control Gene Delivery

利用胶原蛋白重塑途径来控制基因传递

• 批准号: 1159466
• 负责人: Millicent Sullivan
• 金额: $ 42.02万
• 依托单位: University of Delaware
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1159466&HistoricalAwards=false
• 关键词: Utilization; Collagen; Remodeling; Pathways; Control

1159466/ SullivanIntellectual Merit: The overall objective of the proposed project is to develop DNA-linked collagen hydrogels whose remodeling by fibroblast cells will stimulate DNA release and efficient gene delivery. Ultimately, these novel scaffolds will be used to trigger robust (and low cost) in situ expression of growth factors (GFs) to enable healing of chronic wounds and other damaged tissues. In the proposed approach, collagen scaffolds will be modified with plasmid DNAs by newly linking DNA-binding peptides (DBPs) and collagen mimetic peptides (CMPs) with previously established capacities for gene transfer (DBPs) and collagen modification (CMPs). The proposed work will test the following hypotheses: (1) native collagen remodeling processes involving collagen degradation [by matrix metalloproteinases (MMPs)] and collagen endocytosis [by alpha2 beta1 integrins and caveolin-1] will trigger the release and endocytosis of collagen-linked DNA "polyplexes"; (2) collagen linkage will initiate DNA trafficking through efficient gene delivery routes involving caveolin-1. Completion of the proposed aims should provide fundamentally new strategies to understand and direct gene delivery, and in the long term, will foster new materials and therapeutic strategies in tissue repair.Broader Impacts: Given the wealth of target GFs and the widespread use of collagen-based materials, the proposed studies will advance the use of collagen-mediated gene delivery not only in chronic wound repair, but also in multiple other applications such as implant functionalization and regenerative medicine. The proposed efforts are also designed to provide new research and career development opportunities, including industrial mentorship, for undergraduates, high school interns, and underrepresented groups, by building on existing undergraduate research and outreach infrastructure at UD, as well as on previous educational activities of Kiick and Sullivan.

1159466/Sullivan智力优点：拟议项目的总体目标是开发DNA连接的胶原蛋白水凝胶，其通过成纤维细胞的重塑将刺激DNA释放和有效的基因递送。 最终，这些新型支架将用于触发生长因子（GF）的稳健（和低成本）原位表达，以使慢性伤口和其他受损组织能够愈合。 在所提出的方法中，胶原蛋白支架将被修改与质粒DNA通过新连接的DNA结合肽（DBPs）和胶原蛋白模拟肽（CMP）与先前建立的基因转移（DBPs）和胶原蛋白修饰（CMP）的能力。 拟议的工作将测试以下假设：（1）天然胶原重塑过程涉及胶原降解[通过基质金属蛋白酶（MMPs）]和胶原内吞[通过α 2 β 1整联蛋白和小窝蛋白-1]将触发胶原连接的DNA“聚合复合物”的释放和内吞;（2）胶原连接将通过涉及小窝蛋白-1的有效基因递送途径启动DNA运输。 这些目标的实现将为理解和指导基因递送提供全新的策略，从长远来看，将促进组织修复领域的新材料和治疗策略。鉴于靶向GF的丰富性和胶原基材料的广泛使用，所提出的研究将促进胶原介导的基因递送不仅在慢性伤口修复中的使用，而且还可用于多种其它应用，例如植入物功能化和再生医学。 拟议的努力还旨在提供新的研究和职业发展机会，包括工业导师，为本科生，高中实习生和代表性不足的群体，通过建立在现有的本科生研究和外展基础设施在UD，以及在Kiick和沙利文以前的教育活动。