This is an application for competitive renewal of a K05 Senior Scientist Award supporting a longstanding program in research, education and academic development devoted to understanding the fundamental molecular processes underlying actions of drugs of abuse. The research program is related to two Program Project Grants (PPG) in the lab, one on STRUCTURE AND FUNCTION OF NEUROTRANSMITTER TRANSPORTERS (NTs), and the other on HALLUCINOGENS ON 5-HT2A RECEPTORS: MECHANISMS AND EFFECTS. The collaborative, multi-disciplinary scope of the work proposed here involves the development and/or application of powerful state-of-the-art methods for molecular simulation and structure-function analysis, as well as new tools in bioinformatics, computer science, and mathematical modeling for simulation of integrated complex systems (e.g., cellular signal transduction). For the NTs, the long term goal is to understand the systems in a discrete structural context, in a manner that offers mechanistic insight into function at the molecular level. The studies include the dopamine (DAT), serotonin (SERT), norepinephrine (NET), and GABA (GAT) transporters. These are involved in rewarding properties and abuse potential of widely used illicit drugs (e.g., cocaine and amphetamine derivatives such as MDMA), and they also play a central role in mechanisms and treatments of depression and anxiety. The expected insights concerning the molecular mode of operation of the NTs and the modes of ligand interaction will benefit practical considerations of novel pharmacological interventions for treatment and prevention of psychostimulant abuse. For the hallucinogen-focused work, the goal is to understand the molecular mechanism of actions of hallucinogenic drugs of abuse at a level of molecular detail that will enable structure-based design from molecular models of the receptors, and the development - from simulations of mechanisms of action - of effective therapeutic methods of intervention. The studies center on the molecular details of their mechanisms of actions associated with GPCRs, and in particular with 5-HT2A receptors. The proposed work addresses a continuum of interrelated questions, in a common structural context, about function and effects elicited by hallucinogens on various mutant constructs of the human 5-HT2A receptor expressed in cultured cells and in whole animals. The fundamental molecular level of understanding sought for the mechanisms of action of hallucinogens aims to enable efforts in structure-based design of therapeutic modalities against their abuse. In addition, two new projects are being proposed, as high risk/high yield undertakings: One focuses on structural aspects of dimerization in the function of GPCRs, and the other on systems modeling of components of the signaling pathways involved in the cellular mechanisms of hallucinogens.
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