ITR: Gene Design for Vaccines and Therapeutic Phages

疫苗和治疗性基因设计PI：Steven Skiena疫苗和抗生素已被证明分别是对抗病毒和细菌感染的极其重要的制剂。然而，目前的疫苗对某些病毒(如鼻病毒)无效，对其他病毒(如天花)有潜在危险。此外，耐药菌株的进化已经成为治疗结核病等疾病的关键问题。我们建议利用遗传密码中固有的冗余来创造更安全、更有效的疫苗和改进的抗细菌制剂。我们应用设计和合成技术来取代病毒基因，使它们编码与野生型病毒相同的蛋白质，但方式不同。对于第一个应用，我们寻求通过引入突变来弱化病毒株，这些突变改变了翻译效率和RNA二级结构，而不影响蛋白质编码，从而创造出更好的候选疫苗。对于第二种应用，我们试图通过消除重要的限制位点来加强噬菌体(攻击细菌的病毒)，以提高它们对抗病原体感染的能力。Pi(Skiena)是一位计算机科学家，他在理论序列设计问题上做了大量工作，寻求优化的DNA序列，编码特定蛋白质，同时完成其他一些目标。The co-Pi(Wimmer)是一位微生物学家，他在2002年7月完全从现成的成分中合成了脊髓灰质炎病毒，引起了全世界的关注。但是，一旦你可以从头开始合成现有的基因组，你也可以为新的更好的设计做同样的事情。我们将合作进行一系列使用脊髓灰质炎病毒的计算和湿实验室实验，以测试和开发这一愿景。拟议研究的广泛影响包括通过开发新型医疗疗法为社会带来的好处，以及它对跨学科生物信息学教育的影响。

Gene Design for Vaccines and Therapeutic PhagesPI: Steven SkienaVaccines and antibiotics have proven to be tremendously important agents against viral and bacterial infections, respectively. However, current vaccines are ineffective against certain viruses (e.g. rhinovirus) and potentially dangerous against others (e.g. smallpox). Further, the evolution of antibiotic-resistant strains of bacteria has become a critical problem in treating diseases such as tuberculosis.We propose to exploit the redundancy inherent in the genetic code to create both safer and more effective vaccines and an improved class of anti-bacteriological agents. We apply design and synthesis techniques to replace viral genes so they code for identical proteins as in the wild type virus, but in different ways. For the first application, we seek to weaken viral strains by introducing mutations that alter translational efficiency and RNA secondary structure without affecting protein coding so as to create better vaccine candidates. For the second application, we seek to strengthen bacteriophages (viruses which attack bacteria) by eliminating important restriction sites so as to improve their ability to combat pathogenic infections.The PI (Skiena) is a computer scientist who has worked extensively on theoretical sequence design problems which seek optimized DNA sequences which code for a particular protein while simultaneously accomplishing some other objective. The co-PI (Wimmer) is a microbiologist who attracted worldwide attention in July 2002 by synthesizing poliovirus completely from off-to-shelf components. But once you can synthesize an existing genome from scratch, you can do the same for new and better designs as well. We will collaborate on a series of computational and wet lab experiments using poliovirus to test and develop this vision.Broader impacts of the proposed research include benefits to society through developing new types of medical therapeutics, and its impact on interdisciplinary bioinformatics education.