Selena E. Bartlett - US grants

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable disease, disability, and death. Excessive alcohol consumption is the number-three cause of preventable death in the United States. Despite the fact that addiction represents more than 40% of brain-related illnesses, there is a dearth of innovative treatments. Alcohol and nicotine addiction are often treated as separate disorders even though most people with alcohol use disorders also smoke, and continued tobacco use during abstinence from alcohol leads to significantly higher relapse rates. These findings suggest that alcohol and nicotine addictions may develop, and depend on, common pathways. Recently, a large number of human genetic association studies have implicated the neuronal nicotinic receptors (nAChRs), such as the a5 nAChR subunit as playing a critical role in developing alcohol and nicotine dependence processes and recent molecular studies indicate that the a5 nAChR subunit changes the activity of a4b2* nAChRs. Our main objective is to apply a multidisciplinary approach that integrates basic and clinical research to define the molecular basis of the role of nAChRs in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. In the first part of the project, we will combine behavior and electrophysiology studies and there are two objectives: 1) to characterize the role of the a5* nAChRs in the behavioral effects of ethanol and nicotine and varenicline and 2) to measure the expression and synaptic properties of a4b2* nAChRs responses in dopamine neurons in the ventral tegmental area, a brain region that plays a key role in the reinforcing properties of nicotine and ethanol. These studies have been greatly facilitated by an innovative drinking model we developed that enables ethanol and nicotine to be consumed together without the need for saccharin. In the second part of the project, we will combine clinical studies and genetics to determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. There are two major objectives: 1) to measure the effectiveness of varenicline, as a treatment for hazardous alcohol use and 2) to genotype the subjects and assess whether polymorphisms in the genes encoding for nAChRs moderate the effect of varenicline to reduce heavy drinking. The linking of genetic analyses with human responses to varenicline will provide a means by which we can measure both the efficacy of varenicline for diminishing alcohol use disorders and to determine whether there are underlying genetic differences in responses to varenicline. Our overall goal is to accelerate the development of more effective medications, and to improve and personalize treatment strategies for substance use disorders. PUBLIC HEALTH RELEVANCE: We have developed a multidisciplinary collaborative research program focused on defining the molecular basis of the role of neuronal nicotinic receptors (nAChRs) in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. We propose to combine behavior and electrophysiology to define the molecular basis of the role of a5* nAChRs in ethanol and nicotine consumption and determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. The research garnered from this proposal will facilitate the development of medications that target nAChRs for the treatment of alcohol and substance use disorders.

DESCRIPTION (provided by applicant): There is accumulating scientific evidence showing that stressors enhance addictive behaviors and are a common cause of relapse to substance abuse. Corticotrophin releasing factor (CRF) is a 41-aa peptide that has been shown to induce various behavioral changes related to adaptation to stress. The CRF system, including the CRF-binding protein (CRF-BP) and the CRF receptors, CRF-R1 and CRF-R2, are thought to contribute, to the physiological adaptations that result from stress. It has also been shown that CRF interaction with CRF-BP may positively modulate CRF-R2 function and, further that when CRF binds to the CRF-BP, it modulates CRF-R2 signaling and contributes to stress-induced relapse to drug seeking. The aim of this application is to identify a chemical series of ligands and compounds that disrupt the interaction between CRF- BP and CRF-R2 to prevent relapse to drug seeking behaviors. Non-peptidyl chemical inhibitors would have advantages over CRF peptides, in terms of cell permeability, stability, and in vivo pharmacology. In the past, this has been difficult due to an inability to develop a suitable high through-put assay for screening against CRF-BP. To address this problem, we have developed an innovative and novel fluorescence based calcium assay where CRF-BP is expressed and tethered at the cell surface in a heterodimeric complex with CRF-R2. This has greatly facilitated our ability to find molecules that inhibit CRF-R2 activation in the presence and absence of CRF-BP. This innovation forms the basis of the high-throughput assay that we have optimized for chemical library screening. We propose to screen a targeted synthetic compound library using this assay and identify chemical inhibitors of CRF-BP-CRF-R2 receptor complex-mediated signaling. Two types of secondary assays will independently confirm any hits. Structure Activity Relations (SAR) and hit to lead optimization will be performed for prototypical inhibitors of the CRF-BP-CRF-R2 receptor complex leading to exploratory pharmacology and preclinical development. Altogether, these efforts will result in validated chemical probes for studying the biology of CRF-BP-CRF-R2 interaction in a variety of cellular and physiological contexts, with the view to developing new therapeutics for treatment of addiction. PUBLIC HEALTH RELEVANCE: We have developed a multidisciplinary collaborative research program to produce a chemical series of ligands and compounds inhibit the CRF-BP-CRF-R2 receptor complex a novel therapeutic target for the treatment of addiction. We propose to generate research tools for probing the function of the CRF-BP-CRF-R2 receptor complex in the development of addiction. We will combine novel cell based assays, high throughput screening, structure activity relationship analysis, chemistry-based 'hit to lead'optimization to generate a targeted library of novel ligands and compounds. This application will facilitate the development of medications that target the CRF-BP-CRF-R2 receptor complex for the treatment of addiction.

DESCRIPTION (provided by applicant): Alcohol use disorders impact millions of individuals and constitute one of the most serious public health problems worldwide. Despite its devastating impact on society, there are still few effective medications currently available. It is well-known that alcohol and nicotine are commonly abused together, and that ethanol and nicotine have direct affects on neuronal nicotinic acetylcholine receptors (nAChRs). These receptors have been shown to modulate the mesolimbic dopamine system and contribute to the reinforcing actions of both ethanol and nicotine. The nAChRs are pentameric ligand-gated ion channels and in the CNS there are at least twelve receptors, designated 12 to 110, and 22 to 24 that assemble into multiple combinations. My lab discovered that varenicline, a drug that primarily binds to 1422 nAChRs and approved by the FDA as a smoking cessation aid, reduces ethanol self-administration and heavy drinking following long-term ethanol exposure. We will determine the consequences of long-term ethanol exposure on the role and expression of 1422 nAChRs following voluntary heavy ethanol consumption, operant self-administration and in stress- induced reinstatement. We will integrate behavioral and biochemical techniques to identify the brain regions mediating the effects of long-term ethanol exposure on the expression of nAChRs. The long-term goal is to design better therapeutic agents that target nAChRs for the treatment of alcohol use disorders. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are one of the most serious public health problems worldwide. Neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to contribute to the effects of ethanol. We found that varenicline, a modulator of 1422 nAChRs and recently approved as an aid for smoking cessation, reduces ethanol self-administration and heavy drinking following long-term but not short-term ethanol exposure. We will determine whether long-term ethanol exposure induces changes in the expression of 1422 nAChRs and whether this contributes to the reinforcing effects of ethanol and/or stress-induced relapse. The long-term goal is to design more selective and effective medications for the treatment of alcohol use disorders.

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable disease, disability, and death. Despite the fact that addiction represents more than 40% of brain-related illnesses, there is a dearth of innovative treatments, and there is little interest in developing new treatments in the pharmaceutical and biotechnology industry. It is essential that an innovative approach is taken to develop more effective medications for the treatment of nicotine cessation. Our proposed public private partnership (PPP) will provide a comprehensive approach that exploits the latest research discoveries in nicotine dependence and translates this into medications for nicotine cessation. The assembled team has expertise and a demonstrated track record in translating basic research discoveries into medications for addiction in short time-frames. We have developed, implemented and managed a product development pipeline by establishing collaborative partnerships with academic centers, research institutes, government, and private companies. The current cost for developing a new chemical entity is ~$1 billion and as NIDA plans to commit $50 million dollars over 5 years to a public private partnership entity, one of the critical functions of the managing partner will be to raise additional funds by leveraging resources through partnerships. During the UH2 planning phase of the award will form a public private partnership entity that will function as a "virtual pharmaceutical company" devoted to Developing Nicotine Cessation Medicines. By the end of the UH2 phase, we will have established a Board of Directors, advisory boards, established the product development pipeline in consultation with experts in the advisory boards and outside consultants, developed the operations of the organization, establish partnerships via letters of understanding with academic centers and Institutes, pharmaceutical and biotechnology companies, non-government organizations, not-for profit organizations, Foundations and international relations with countries such as China, where the prevalence of smoking is so great it is considered a significant health and economic threat for the country. At the end of the UH2 planning phase the managing partner (MP) will be ready to implement the product development pipeline at the beginning of the UH3 phase. The mission of the PPP will be "patient focused and medicines centered". The product development pipeline will have 10 projects operating simultaneously with the view of developing two new medicines for nicotine cessation. The development process differs significantly in its approach from that of the academic lab and favors a more linear, project management style. The strategy will be to focus on the project at hand, as each project requires a unique array of components for translation. We will draw on the wealth of information from basic and clinical research generated from model organisms such as rodent models, discoveries in molecular neuroscience, systems neuroscience, genetics and clinical research. We have established extensive industry collaborations to source and synthesize compounds using contract chemical companies, biotechnology and pharmaceutical companies that have drug development and clinical trial expertise. The goal will be to develop medicines for addiction by accelerating the pathway of basic research discoveries to the clinic. It is not possible to develop medicines without collaborating with business for intellectual property, licensing and investment as this endeavor needs significant funds and resources. The Gallo Center, the Sanford Burnham Medical Research Institute and University of California San Diego have demonstrated track record as collaborative partners, have experience with a successful bench-to-bedside program for the development of novel therapeutics. Together we have established a medications development program that extends from basic research in addiction, preclinical development, drug discovery and development to human clinical trials. Furthermore, technologies are developed through intellectual property licensing and joint development relationships with biotech and pharmaceutical companies. If we are given the opportunity, we will develop a multidisciplinary collaborative public private product development partnership that aims to move from molecules to medicines by applying a virtual pharma approach to develop novel medications for nicotine cessation. PUBLIC HEALTH RELEVANCE: Despite the fact that by 2030 around 10 million people a year will die of smoking-related illness, there is a dearth of innovative treatments, and relatively little interest in developing new treatments in the pharmaceutical and biotechnology industry. We will develop a multidisciplinary collaborative public private product development partnership that aims to move from molecules to medicines by applying a virtual pharma approach to develop novel medications for nicotine cessation.