The goal of the proposed research is to developing a therapy for cocaine abuse with a modified human butyrylcholinesterase (BChE) rationally mutated into an efficient hydrolase that metabolizes cocaine into hypoactive products (benzoic acid and ecgonine methyl ester). To enable testing in primates we will need pure enzyme in large quantities. To this end we are proposing to use technology we developed at Arizona State University (ASU) that allows production of gram quantities of human BChE, with desired mutations, in transgenic plants (Nicotiana benthamiana). We will further experiment in enhancing the stability of these plantderived proteins with appropriate post-translational and chemical modifications, rendering them highly suitable for the in vivo tests that are planned. As a protein biochemist and molecular biologist, I have been working on plant production of pharmaceutically important proteins for over 13 years first as a postdoc at the Boyce Thompson Institute then in my own lab at ASU. Particularly, I have been developing platforms for the production of cholinesterases, both acetylcholinesterase (AChE) and BChE, first as a PI on a DARPA contract, and currently as a PI of a project which is part of a CounterACT (NIH) Center of Excellence. We have extensively published in peer-reviewed journals on this newly developed technology and have issued and pending patents covering it. One of the patents, involving production of AChE in plant cells was recently licensed to a company that is taking the product to clinical trials. Through these previous and active federallyfunded grants, I laid the groundwork for the proposed research by exploring plant-derived BChE and AChE as bioscavengers of OP nerve-agents, rationally-designing mutants and variants for high level expression and accumulation in plants, developing purification protocols, and IACUC-approved animal study protocols. I have been engaged throughout my academic career in several multidisciplinary, multi-investigator, and multiinstitutional projects and have gained much experience in their administration (directing students and technicians, report writing, budget management etc.). I am very comfortable in collaborative work, both toward achieving milestones, keeping to timeline, producing deliverables both in the terms of generation of research materials as well as in terms or reportable outcomes (e.g. joint peer-reviewed publications). In summary, I have the necessary expertise and experience, demonstrated by successful previous and on-going research.2
|Effective start/end date||9/30/10 → 10/29/11|
- HHS: National Institutes of Health (NIH): $129,729.00
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