Discovery of a Platelet Derived Growth Factor Peptide-based Mimetic

发现基于血小板衍生生长因子肽的模拟物

• 批准号: 7210480
• 负责人: PAUL T HAMILTON
• 金额: $ 23.54万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210480
• 关键词: bioengineering /biomedical engineering; biological signal transduction; biomaterial development /preparation; biomaterial evaluation; biomimetics; biotherapeutic agent; collagen; diabetes mellitus therapy; drug discovery /isolation; foot; growth factor receptors; medical complication; peptide chemical synthesis; peptide library; peptides; phage display; platelet derived growth factor; protein binding; protein sequence; protein structure function; receptor binding; tissue /cell culture; ulcer; wound healing

DESCRIPTION (provided by applicant): Project Summary/Abstract: Diabetic foot ulcers are a significant health problem that imposes high costs on both patients and society (Boulton, Vileikyte et al. 2005). A large proportion of foot ulcers remain unresponsive to available conventional treatment and their associated complications and costs have prompted extensive research that has led to promising breakthroughs. Recombinant growth factors, biodegradable matrices, and bioengineered skin equivalents have been developed to better promote healing (Edmonds, Bates et al. 2000). These therapies have shown promise, but still have limitations including high cost, immunogenicity, and the need for high, repeated doses of growth factor. Platelet Derived Growth Factor (PDGF) is a potent chemotactic, mitogen, and differentiation factor that promotes soft tissue formation and rhPDGF-BB is currently FDA approved to treat diabetic ulcers. Repeated application of high dose PDGF increases the cost and complexity of treatment. In general, biologic therapeutics are more expensive to develop and manufacture than synthetic therapeutics. Therefore, a synthetic alternative that also has a longer resident time could significantly reduce the cost and complexity of current therapies. The goal of this proposal is to generate a PDGF-BB mimetic that can be immobilized on a collagen scaffold used to promote soft tissue and wound healing. We plan to use phage display technology to identify peptides that mimic PDGF-like signaling of the PDGF B-receptor. These peptides will be linked to a previously identified high-affinity, collagen-binding peptide. The resulting hybrid molecule is expected to allow controlled, local delivery of a synthetic molecule from the surface of a collagen matrix. We expect that collagen binding peptides will significantly improve the retention of a bioactive PDGF mimetic in a wound. First, using phage display techniques, we will identify peptides that bind to the PDGF B-receptor. Secondly, to increase the affinity of the peptides for the B-receptors, focused libraries will be constructed based on the sequences of the initial B-receptor-binding peptides and screened again on the B-receptors. Next, synthetic peptides containing 2 copies of the B-receptor binding sequence will be chemically synthesized with a flexible linker and the resulting dimers will be tested for PDGF-BB-like activity with a fibroblast proliferation assay. Finally, we will synthesize combinations of Affinergy's existing collagen binding sequences and the newly identified PDGF-BB mimetic peptide and the hybrid molecule will be tested for binding to collagen and for its ability to induce fibroblast proliferation while bound to a collagen matrix. Project Narrative: Diabetic foot ulcers are a significant health problem that imposes high costs on both patients and society. A large proportion of foot ulcers remain unresponsive to conventional treatment and have prompted research that has led to promising breakthroughs, including recombinant growth factors, biodegradable matrices, and bioengineered skin equivalents. These therapies have shown promise, but still have limitations including high cost, immunogenicity, and the need for high doses of growth factor. In this project, we will develop a Platelet Derived Growth Factor (PDGF) peptide-based mimetic that can be immobilized on a collagen scaffold used to promote wound healing. We plan to use phage display technology to identify peptides that mimic PDGF's biologic activity. In general, biologic therapeutics are more expensive to develop and manufacture than synthetic therapeutics. Therefore, a synthetic alternative that also has a longer resident time could significantly reduce the cost and complexity of current therapies.

描述(由申请人提供)：项目摘要/摘要：糖尿病足部溃疡是一个严重的健康问题，对患者和社会都造成了高昂的成本(Boulton，Vileikyte等人。2005)。很大比例的足部溃疡仍然对现有的常规治疗没有反应，其相关的并发症和成本促使了广泛的研究，导致了有希望的突破。重组生长因子、可生物降解基质和生物工程皮肤替代品已经被开发出来，以更好地促进愈合(Edmonds，Bates等人)。2000)。这些疗法已经显示出希望，但仍然存在局限性，包括高成本、免疫原性，以及需要高剂量、重复剂量的生长因子。血小板衍生生长因子(PDGF)是一种强大的趋化、丝裂原和分化因子，可促进软组织形成，而重组人PDGF-BB目前已被FDA批准用于治疗糖尿病溃疡。反复应用大剂量的PDGF增加了治疗的成本和复杂性。一般来说，生物疗法的开发和制造比合成疗法更昂贵。因此，一种驻留时间更长的合成替代品可以显著降低当前疗法的成本和复杂性。这项提议的目标是产生一种PDGF-BB模拟物，可以固定在用于促进软组织和伤口愈合的胶原蛋白支架上。我们计划使用噬菌体展示技术来识别模拟PDGFB受体的PDGF样信号的多肽。这些多肽将与先前发现的一种高亲和力的胶原蛋白结合肽相连。由此产生的杂化分子有望允许合成分子从胶原基质的表面进行受控的局部输送。我们预计，胶原结合多肽将显著改善具有生物活性的PDGF模拟物在伤口中的保留。首先，使用噬菌体展示技术，我们将识别与PDGFB受体结合的多肽。其次，为了增加多肽与B受体的亲和力，将根据最初的B受体结合肽的序列构建焦点文库，并在B受体上进行再次筛选。接下来，含有2个B受体结合序列拷贝的合成肽将用柔性连接物化学合成，所得二聚体将用成纤维细胞增殖试验测试PDGF-BB样活性。最后，我们将合成AffinEnergy现有的胶原结合序列和新发现的PDGF-BB模拟肽的组合，并将测试杂交分子与胶原的结合以及在与胶原基质结合时诱导成纤维细胞增殖的能力。项目简介：糖尿病足溃疡是一个严重的健康问题，给患者和社会带来了高昂的成本。很大比例的足部溃疡仍然对传统治疗无效，并已促使研究取得有希望的突破，包括重组生长因子、可生物降解的基质和生物工程皮肤替代品。这些疗法已经显示出希望，但仍然存在局限性，包括高成本、免疫原性和需要高剂量的生长因子。在这个项目中，我们将开发一种基于血小板衍生生长因子(PDGF)多肽的模拟物，它可以固定在用于促进伤口愈合的胶原支架上。我们计划使用噬菌体展示技术来识别模拟PDGF生物活性的多肽。一般来说，生物疗法的开发和制造比合成疗法更昂贵。因此，一种驻留时间更长的合成替代品可以显著降低当前疗法的成本和复杂性。