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SYNTHETIC BZIP PROTEINS AS TARGETING AGENTS FOR PDT

合成 BZIP 蛋白作为 PDT 靶向药物

基本信息

批准号：
6028232
负责人：
MICHAEL Y OGAWA
金额：
$ 9.09万
依托单位：
BOWLING GREEN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2003-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6028232
关键词：
DNA binding protein drug delivery systems gel mobility shift assay intracellular transport metal complex metalloproteins neoplasm /cancer photoradiation therapy nucleic acid sequence peptide chemical synthesis synthetic protein transcription factor transport proteins

项目摘要

The following proposal for a NIH-AREA grant describes a pilot study designed to test the efficacy of utilizing the family of bZIP transcription factors to target photodynamic therapy (PDT) reagents to specific sequences of DNA (i.e. the AP-1 element: 5'-TGAGTCA-3'). In particular, both native and de novo designed bZIP proteins will be derivatized with photoactive metal complexes which have been previously shown to cause DNA damage by either direct photoinduced electron-transfer and/or the photochemical generation of singlet oxygen (1O2). The in vitro DNA recognition properties of these metallopeptides will then be studied by electrophoretic mobility shift assays, as will be their ability to produce site-specific DNA photodamage. Transient absorption and emission lifetime studies will be conducted on these systems to help identify the mechanisms involved in the photolesion process. An advantage in using bZIP proteins as targeting vehicles for PDT reagents is that their recognition elements can be found within a large number of promoters which participate in such important processes as cell differentiation and proliferation. Damage to these sites should be very cytotoxic. An additional advantage in the proposed approach to deliver PDT drugs to specific intracellular targets is that it can, in principle, be used to deliver a wide variety of PDT drugs. It is believed that the work described in this proposal will provide a new opportunity for students at Bowling Green State University to participate in a multi-disciplinary research project which may encourage their interest in pursuing graduate studies in the biomedical sciences. Receipt of this award will also enhance the PI's ability to pursue the goals of this focused pilot-project.

以下NIH-AREA资助的提案描述了一项试点研究，旨在测试利用bZIP转录因子家族将光动力治疗（PDT）试剂靶向特定DNA序列（即AP-1元件：5 '-TGAGTCA-3'）的功效。特别是，天然和从头设计的bZIP蛋白质将与光敏金属络合物衍生化，所述光敏金属络合物先前已显示通过直接光诱导电子转移和/或单线态氧（1 O2）的光化学产生引起DNA损伤。这些金属肽的体外DNA识别特性，然后将通过电泳迁移率变动分析进行研究，因为将是他们的能力，产生特定位点的DNA光损伤。将对这些系统进行瞬态吸收和发射寿命研究，以帮助确定光解过程中涉及的机制。使用bZIP蛋白作为PDT试剂的靶向载体的优点在于，它们的识别元件可以在大量参与细胞分化和增殖等重要过程的启动子中发现。这些部位的损伤应该具有很强的细胞毒性。所提出的将PDT药物递送至特定细胞内靶点的方法的另一个优点是，原则上，它可以用于递送各种各样的PDT药物。据信，这项建议中所描述的工作将提供一个新的机会，让学生在保龄球绿色州立大学参加一个多学科的研究项目，这可能会鼓励他们在生物医学科学研究生学习的兴趣。获得该奖项也将提高PI追求这一重点试点项目目标的能力。