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2014 March

Innate DNA Demethylation Capacity as a Contributor to Smoking Initiation

Susan Searles Nielsen, PhD
Environmental and Occupational Health Sciences

Federico M. Farin, M.D.
Environmental and Occupational Health Sciences

Theo A. Bammler, Ph.D.
Environmental and Occupational Health Sciences

Description: Despite the massive negative public health impact of tobacco use, and substantial difficulties in achieving long term cessation, relatively little is known about biological factors that contribute to smoking initiation. Identification of contributors may facilitate the development of prevention strategies, and possibly suggest new avenues of research on smoking cessation. Data from a population-based study in western Washington State provide evidence that an innate enhanced ability to demethylate DNA may contribute to smoking initiation. We propose to use validated smoking data and archived mononuclear cells from neurologically normal participants to efficiently assess whether increased expression of the ten-eleven translocation methylcytosine dioxygenase (TET) family of genes is associated with greater smoking initiation. TETs are the primary enzymes responsible for the active demethylation of DNA, including throughout the brain and in other regions of the body that may alter initial response to nicotine and other constituents in tobacco smoke. Notably, TETs increase the expression of many “immediate early genes,” genes activated transiently and rapidly in response to a wide variety of cellular stimuli, and which largely code for transcription factors that can affect genes across the genome. These potentially include, for example, genes coding for brain-derived neurotrophic factor, nicotinic acetylcholine receptors, dopamine receptors and transporters, enzymes involved in nicotine metabolism, and receptors involved in olfaction, taste, oral pain sensitivity, and cough response. Secondarily, this study will examine the relation between TET expression and global DNA methylation, as assessed by existing data on LINE-1 methylation for these same subjects, to attempt to confirm prior research that indicates that demethylation is a mechanism by which TET alters gene expression.

Results from the proposed work will build a foundation for expanded investigations using this existing study, and support the initiation of a new epidemiologic study specifically designed to further elucidate biological contributors to smoking initiation.

Resulting articles & projects:

  • The PI along with Co-I’s on the present proposal recently submitted a larger pilot proposal to the University of Washington Center for Ecogenetics and Environmental Health (CEEH) (PI Searles Nielsen, Co-I’s Bammler and Longstreth). The pilot data from the present proposal was instrumental in preparing a successful pre-proposal application, and for the ultimate invited proposal itself. That proposal is currently under review (Feb-Mar 2015). If funded, this companion project would synergize with the work conducted under the ADAI pilot study. Notably, this second project would nearly double the sample size for three of the five genes included in the ADAI project. Secondarily, gene expression data for these three genes from the ADAI pilot project will be used as the “gold standard” to validate gene expression results using a higher throughput method. The purpose of this expanded pilot work is to increase the probability of success of extramural funding by strengthening our results on smoking initiation and two of the genes (described above) and to investigate whether this alternative laboratory method could be used in the context of a much larger study to make the work more economical. NIH is the main target for the present work, primarily NIDA, but we also anticipate possible smoking-related proposals to NINDS, NIEHS and NIOSH. The latter would be focused on occupational chemical exposures that may possibly contribute to greater smoking through their effects on expression of the above genes. Such proposals, if funded, would almost certainly result in additional data useful for the proposal to NIH-NIDA. The proposals will likely be R03, R21 and K22 proposals. Submission of a proposal to NIH is anticipated following publication of a manuscript.

Using Text Message Reminders to Help Adolescents Remain Mindful of Their Commitment to Drug Abstinence

Frank J. Schwebel, B.S., Graduate Student

Mary E. Larimer, PhD, Professor, Psychiatry & Behavioral Sciences (Mentor)

Description: Substance abuse is a major health and safety problem that most commonly begins during adolescence. Substance abuse during adolescence can lead to many short and long-term negative consequences including altered academic and employment trajectories, incarceration, susceptibility to future drug problems, cortical damage, and impaired adult cognitive functioning.

Relapse prevention is currently the standard treatment for adolescent substance abusing and substance dependent individuals who have chosen abstinence. Reminders of one’s commitment to abstinence, such as alarm clocks and calendars can serve as support mechanisms for relapse prevention. With the advent of new technology (e.g., cellphones), the potential arises to update these reminder mechanisms. Because adolescents are often first adopters of new technology, new reminder methods may be particularly effective with them. Research on applying technology to substance abuse treatment has focused on the effect of text-message interventions for individuals not seeking treatment. We are aware of no studies investigating the effect of texting as a support mechanism for substance abuse relapse prevention. The current study proposes to apply text messages as a supportive reminder and adjunct to substance abuse counseling with adolescents. Three groups (N = 150) will be compared: a treatment as usual control condition (N = 50), a group of youth who self-select their messages (N = 50), and a yoked group who are assigned messages (N = 50). Messages will be sent in a random order and at randomized time intervals for four weeks. Data collected through this study will examine the impact of text message content on relapse rates. Data also will be gathered to measure the impact of the messages on self-efficacy and receptivity of youth to these messages.

These data will provide preliminary findings necessary to seek external funding to develop a larger scale RCT of text messaging in support of relapse prevention.

Automated Screening and Collaborative Care in the ED for Trauma Patients With Prescription Drug Misuse: An Open Feasibility Trial

Lauren K. Whiteside, MD
Harborview Medical Center

Dennis M. Donovan, Ph.D., Psychiatry & Behavioral Sciences

Douglas Zatick, M.D., Psychiatry & Behavioral Sciences

Description: In 2012, approximately 6.8 million Americans reported prescription drug misuse (PDM) in the past month, which exceeds the number of Americans abusing cocaine, heroin, hallucinogens, and inhalants combined. Injured trauma patients in the ED may be a particularly important group to target for screening and intervention for PDM. These patients have high rates of psychiatric and substance use co-morbidity and pain management for their injuries will require prescribed opioid analgesics and other controlled substances.

To date, there are no effective ED-based interventions for PDM. Collaborative Care is a longitudinal model of care that combines medication management, care linkage and care management for patients with complex medical comorbidities. This model holds promise as an intervention strategy for injured patients in the ED with the complex comorbidity of PDM. Collaborative Care and longitudinal care management from the ED is innovative and requires developing follow up procedures on a population that has previously been difficult to follow and may have previously avoided consistent health care delivery. This proposal aims to establish the feasibility of a collaborative care intervention (RxCC) to reduce PDM by conducting an open pilot trial for injured patients (n=30) at elevated risk for PDM, and then develop successful follow-up procedures for these patients in the trial to deliver longitudinal care. The primary outcomes will be intervention feasibility and acceptability as well as retention rates at 1-, 3-, and 6-month follow up time points and the number of contacts made with the patient within the collaborative care framework. Secondary outcomes to be assessed in this open trial include patient satisfaction with the intervention, health care utilization and substance use outcomes over 6 months.

This proposal addresses a gap in research on effective interventions for PDM and provides an innovative approach to screening and intervention for this complex problem from the ED.

Resulting articles & projects:

  • In August 2015, Dr. Whiteside was awarded a K23 (K23DA039974) from the National Institute of Drug Abuse (NIDA). The mentors on her K23 (Dr. Doug Zatzick and Dr. Dennis Donovan) also helped with on the ADAI small grant project.
  • Whiteside LK, Darnell D, Jackson K, Wang J, Russo J, Donovan DM, Zatzick DF. Collaborative care from the emergency department for injured patients with prescription drug misuse: an open feasibility study. J Subst Abuse Treat 2017;82:12-21. doi: 10.1016/j.jsat.2017.08.005.
  • Whiteside LK, Darnell D, Jackson K, Donovan D, Zatzick DF. Collaborative Care from the ED for Trauma Patients with Prescription Drug Misuse: A Feasibility Study. Poster presented at University of Michigan Opioid Overdose Summit, December, 2015.
  • Whiteside LK, Darnell D, Jackson K, Donovan DM, Zatzick DF. Collaborative Care for Injured Patients with Prescription Drug Misuse: A Feasibility Pilot, presented at College on Problems of Drug Dependence, June 2016.

2014 October

College Student Veterans’ Alcohol Use and Academic Reintegration: A Mixed Model Methods Approach

Ty W. Lostutter, PhD, Assistant Professor
Psychiatry & Behavioral Sciences

Description: The broad, long-term objective of this research is to develop an efficacious intervention to address alcohol, which will include a module on smoking for whom it is relevant, and psychiatric symptoms (Post Traumatic Stress Disorder, PTSD and depression) for returning Operating Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans pursuing their postsecondary education.

To accomplish this objective the research project is divided into two phases with the following aims: 1) Conduct a web-screening survey of OEF/OIF college students on key constructs related to alcohol (including quantity, frequency, and consequences), smoking, psychiatric symptoms (PTSD and depression), student veteran identity, and academic performance. 2) Conduct qualitative interviews and focus groups to provide rich contextual data to provide a deeper understanding of the role alcohol, smoking and psychiatric symptoms play in relation to academic performance. Qualitative interviews and focus groups will also explore the OEF/OIF students’ preferences for content and format of indicated prevention programs to guide future intervention development endeavors.

Furthermore, secondary analysis of existing data from a previously funded pilot project of OEF/OIF college student population will be incorporated with data from the proposed project to conduct data triangulation analyses, in order to develop a model specifically designed to guide development of an alcohol, smoking, and mental health intervention for college student veteran populations.

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