A Nanomachine for Repair of Human DNA (RMI)

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The goal of nanomedicine is to use a detailed knowledge of molecular machines in molecular intervention for treating disease and repairing damage. We propose to establish a center to dissect the operation of a nanomachine that carries out a major DNA repair process in human cells. This process is called nucleotide excision repair (NER), and it involves at least 25 protein factors. The knowledge gained about the NER machinery will be harnessed for application to nanomedicine. In this Concept Development Memo we first outline compelling reasons for undertaking an intensive study of the NER nanomachine in relation to human health. We identify some emerging questions and gaps in existing knowledge. The proposed investigations will be carried out initially by four working groups of scientists: Biochemistry, Structural Biophysics, Advanced Measurement and Imaging Science, and Computational Molecular Biophysics. Each of these groups will be formed around a core of scientists drawn from the University of Pittsburgh and from Sandia National Laboratories. Particular strengths at the University of Pittsburgh include imaging, computational biology, biochemistry and single-molecule manipulation of DNA, while Sandia Labs is noted especially for strengths in biomoiecular materials and interfaces, chemical synthesis and nanomaterials, and the science and technology of microsensors. Together, this group of investigators will form a powerful force in development of the new field of nanomedicine. A major goal is to develop tools for analysis of the NER nanomachine that can be utilized to investigate other cellular machines relevant to nanomedicine. The requested funds will be used to facilitate the interactions of scientists and engineers in preparing a Concept Development Plan for submission to NIH as the next step in developing a Nanomedicine Center.