A Novel Toolbox of Gene Expression Systems Applicable to Multimodality Molecular-Genetic Imaging

我的研究项目涉及一个新兴的科学领域，称为分子遗传成像，重点是开发基于DNA的分子，称为基因载体，以成像体内深处的细胞和分子。这些基因载体在实验室中被改造成称为成像报告分子的分子，这些分子可以被各种成像扫描仪检测到，并有两个主要应用。首先，它们可以被设计成当它们被注射到体内时，它们允许人们看到特定细胞的位置，它们的行为方式，以及它们的位置和数量是否随时间而变化。其次，人们可以使用这些载体来标记在实验室中生长的细胞，这样当这些细胞被引入体内时，人们就可以进行成像，以跟踪它们的最终位置以及它们如何与其他组织相互作用。推动这一领域向前发展的关键是基因载体的生产，这些载体可以使成像报告分子处于最高可能水平，并且对正常细胞功能没有任何负面影响。通过这种方式，我们可以检测到尽可能少的细胞，而不会产生任何毒性作用。目前，我们还没有这样的工具用于分子遗传成像应用。考虑到这一基本限制，我的研究计划将开发一个新的强大和无毒的基因载体工具箱，这将有助于克服这两个关键瓶颈。具体来说，我将开发和优化几种最先进的报告基因载体，称为微环（MC），自我复制的MC，整合酶缺陷型慢病毒载体（IDLV）和自我复制的IDLV;所有尖端载体在我的领域没有被广泛探索。我还专注于开发表达多种报告基因的载体，这些报告基因可以用各种成像机器检测到，因此它们将有助于尽可能多的应用。我的长期目标是不断发展这些技术，并在动物模型中测试最佳系统，对加拿大和世界各地的临床成像问题产生长期影响。总之，我的研究将解决有关不同基因载体用于分子遗传成像的有效性和局限性的基本问题。考虑到在学术和工业环境中对分子遗传成像技术的新兴兴趣，我的计划处于有利地位，可以在重要试剂的创新方面做出关键贡献。

My research program deals with an emerging field of science called molecular-genetic imaging that focuses on the development of DNA-based molecules called gene vectors to image cells and molecules deep within the body. These gene vectors are engineered in the lab to make molecules called imaging reporters that are detectable with a variety of imaging scanners and have two main applications. First, they can be designed in a way that when they are injected into the body they permit one to see where specific cells are located, how they are behaving, and if their location(s) and numbers change over time. Secondly, one can use these vectors to tag cells grown in the lab so that when these cells are introduced into the body one can perform imaging to track where they end up and how they are interacting with other tissues. Critical to moving this field forward are the production of gene vectors that can make imaging reporter(s) at the highest possible levels and do not have any negative effects on normal cell function. This way we can detect the fewest number of cells possible without any toxic effects. Currently we do not have such tools for molecular-genetic imaging applications. With this fundamental limitation in mind, my research program will develop a new toolbox of powerful and non-toxic gene vectors that will help overcome these two critical bottlenecks. Specifically, I will develop and optimize several state-of-the-art reporter gene vectors called minicircles (MCs), self-replicating MCs, integrase-defective lentiviral vectors (IDLVs), and self-replicating IDLVs; all cutting-edge vectors that not been extensively explored in my field. I am also focused on developing vectors that express multiple reporters that are detectable with an assortment of imaging machines so they will be useful for as many applications as possible. My long-term goals are to continually evolve these technologies and test the optimal systems in animal models, with the potential for long-term impact in clinical imaging problems both in Canada and around the world. In summary, my research will address fundamental questions concerning the effectiveness and limitations of different gene vectors for molecular-genetic imaging. Considering the emerging interest in molecular-genetic imaging technologies in both academic and industrial settings, my program is well positioned to make critical contributions in the innovation of important reagents.