A concept describes the purpose, scope, and objectives of a potential funding opportunity. Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research. Concepts are being posted to give interested researchers additional time to plan for application submissions.
Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.
- HIV-Associated Neuropathic Pain and Opioid Interaction
- Pharmacogenomics of Immune Recovery in People Who Inject Drugs (PWID)
- Identification of Immune and CNS Biomarkers of HIV Infection and Substance Abuse Comorbidity
- Exploring Novel RNA Modifications in HIV/AIDS and Substance Abuse
- Limited Competition-Cohorts of HIV/AIDS and Substance Abusing Populations
- HIV/HCV Co-infections in Substance Abusers
- Development of Clinical Research Tools to Accurately and Objectively Measure Pain
- Wearable to Track Recovery & Relapse Factors for People with Addiction
With increased survival of HIV-infected patients due to antiretroviral therapy (ART) there is an increase in those living with neuropathic pain. Despite long-term ART, low levels of viral replication persists in CNS HIV reservoirs resulting in constant release of neurotoxic HIV proteins, including Tat and gp120. These toxic proteins have potential to contribute to neuropathic pain directly via inducing neuronal damage and indirectly via glia activation. In addition, HIV-infected opioid abusers appear to exhibit more severe neuropathy than HIV-infected non-drug users and repeated use of opioid analgesics promote chronic pain in HIV patients. The purpose of this RFA is to promote research investigating the underlying cellular, molecular, genetic, and epigenetic mechanisms whereby opioids including prescription drugs exacerbate HIV-associated neuropathic pain. Some of the proposed mechanisms are upregulation of TLR4, CXCR4, and CCR5 receptors and increased transfer of intestinal bacteria to the peripheral circulation. The ultimate goal is to obtain information for developing safe and effective treatments of neuropathic pain for HIV-infected patients exposed to opioids.
Vishnudutt Purohit - Program Officer, Integrative Neuroscience Branch/Division of Neuroscience and Behavior
Twenty percent of HIV infected individuals who successfully suppress plasma viremia below the limits of detection do not recover sufficient CD4+ T cell counts. The failure to recover normal CD4+T cells after anti-retroviral therapy is associated with intravenous drug use. Poor CD4+T cell recovery is associated with increased mortality and morbidity that has a genetic component. The goal of this funding opportunity is to identify genetic variants and epigenetic modifications affecting failure of recovery of CD4+T counts (<200) in PWID/HIV+ and PWID-/HIV whose viral load has been suppressed by ART for two years using existing resources or doing a prospective study. The resulting study will also provide information about gene by intravenous drug use interaction on recovery of CD4+ T cell count.
Dr. Jonathan D. Pollock - Branch Chief, Genetics, Epigenetics, and Developmental Neuroscience Branch/Division of Neuroscience and Behavior
Research Objectives: The FOA fosters biomarker research to advance clinical assessment of damages and functional reservation of host defense mechanism and comorbid complications at different phase of HIV-1 pathogenesis. Neuroimmunological profiling study is encouraged for comprehensive evaluation of blood and CSF soluble and cellular proteins and other molecules that change during HIV infection and accompanying inflammatory and neurodegenerative alterations. The study will enable identification of a set(s) of biomarkers that reflect the degree of damage and functional resilience ability of the defense system, and that will facilitate establishment of standards, and normal range of clinical lab tests that can detect early signs, and differentiate level of functional and structural deterioration of the compromised immune and neural system.
Background: HIV infection and chronic use of drugs of abuse (SUD) both change biological homeostasis and host defense mechanism. Current knowledge about the underlying inflammatory and degenerative process is largely based upon observations from small samples, suggesting altered signaling of a handful of pro-inflammatory and neurodegenerative molecules correlated with the diseases. The correlational data has limited clinical value, especially when information on molecules with anti-inflammatory or neuroprotective action is missing. A comparative assessment of blood and CSF samples will permit initial characterization and screen of molecular markers most representative of the compromised defense mechanism. The findings can then be validated by proof-of-concept studies to facilitate formation of a panel(s) of signatures that can be used for objective and quantitative assessment of disruptions in immune and neural system, and prediction of general immunity and functional resiliency of the patients.
Yu ‘Woody’ Lin, Ph.D. - Program Official, Integrative Neuroscience Branch/DNB
Background: Recent evidence suggests that certain RNA modifications have important biological and disease functions in mammals. Most covalent RNA modifications remain poorly characterized, although they are likely to influence RNA properties and functions such as RNA stability, trafficking, localization, activity, and patterns of interactions with other molecules. RNA modifications play a role in a variety of brain diseases including depression, schizophrenia, and addiction-relevant behaviors. For example, Fat Mass and Obesity (FTO), enzymatically demethylates m6A in RNA, an activity that alters dopamine function in mouse midbrain and striatum (Hess et al. 2013 Nature Neuroscience 16:1042-8).
RNA modifications of the HIV RNA genome have been poorly characterized until recently. One research team has shown that depletion of enzymes that “write” the RNA modification m6A leads to decreased HIV replication as a result of decreased export of the m6A modified HIV RNA genome from the nucleus into the cytosol (Lichinchi et al. 2016 Nature Microbiology 1:article 16011). Furthermore they found significant changes to m6A levels on host mRNAs involved in the HIV-relevant processes. Meanwhile, another team has found that m6A reader proteins can inhibit HIV infection in cell lines and decrease HIV gag protein expression (Tirumuru et al. 2016 eLife 10.7554/eLife.15528). The mechanisms of m6A regulation in HIV/AIDs is very much under investigation. However there are at least three dozen additional RNA modifications in mammalian cells, and their role in HIV/AIDs and/or substance abuse is not known.
Proposal: This proposal is designed to support exploration to see if any of the three dozen known mammalian RNA modifications also play roles in HIV infection, replication, or in HIV/AIDs disease progression. It will also support hypothesis-driven investigations to better understand how m6A and other better characterized RNA modifications function in HIV-relevant processes. Researchers will investigate the mechanisms by which HIV/AIDS-relevant RNA modifications may interact with chronic drug exposure and/or substance use disorders. The enzymes that read, write, and erase RNA modifications have evolved to bind to small molecules and are thus potentially druggable targets. Research in this area may lay the foundation for identifying novel HIV/AIDS therapeutic targets in the future.
John Satterlee, Ph.D. - Acting Deputy Director, Division of Neuroscience and Behavior
Description/Justification: Through PAR12-222, the National Institute on Drug Abuse supported a number of cohorts of HIV/AIDS and substance abusing populations to address emerging and high priority research on HIV/AIDS and other opportunistic infections. These cohorts continue to serve as a strong resource platform for current and future collaborative efforts with other investigators to address emerging questions related to HIV infection, prevention, and treatment in the context of substance abuse, as well as to foster the creativity and efficiency of investigator-initiated research. The purpose of this Limited Competition Funding Opportunity Announcement (FOA) is to support: (i) the maintenance of NIDA-funded existing cohorts to continue to address new emerging and/or high priority research on multidisciplinary aspects of HIV/AIDS and substance abuse, (ii) provide support for retaining HIV/AIDS infected substance abusing populations into the cohort(s) to provide insight into the demographics of the HIV epidemic among this high risk population in the US; (iii) encourage applications from: current cohort investigators This FOA will continue to provide a strong resource platform for current and future collaborative efforts with other investigators to address new and emerging questions related to HIV infection, prevention, and treatment in the context of substance abuse, as well as to foster the creativity and efficiency of investigator–initiated research goals.
Research areas: The proposed FOA will support multi-disciplinary multi-component basic, behavioral, and clinical research to cover multiple areas of research including but not limited to: (i) impact of community or individual level treatment and prevention modalities related to substance abuse and HIV/AIDS, (ii) engagement and retention in care, adherence to treatment regimens, (iii) study HIV and OI-disease progression and outcomes, (iv) impact of long-term drug use on progression of HIV/AIDS and other OI-related disease; (v) immunologic and virologic responses to HIV therapy, (vi) progression of HIV, HIV/HCV disease, (viii) infections associated medical and health consequences (neuro AIDS, cardiac, hepatic, renal, drug-drug interactions etc.) in drug abusing populations; and (ix) study impact/role of microbiome in HIV and HIV/HCV infections in substance abusing populations.
Dr. Jag Khalsa, MS, Ph.D. - Chief, Medical Consequences of Drug Abuse and Co-occurring Infections Branch/Division of Therapeutics and Medical Consequences, NIDA
Description/Justification: Currently an estimated 33 million people worldwide are living with HIV infection and 135 million people are living with HCV infection. In the US, the corresponding number of people with HIV and HCV infection are 1 and 3-4 million, respectively. An estimated 50,000 new cases of HIV and 30,500 are newly diagnosed or incident cases of HCV infection in the US. Substance abuse plays a major role in acquisition and transmission of HIV/HCV co-infection with highest incidence in persons with substance use disorders (SUDs). As many as 45-60% people with SUD are infected with HIV or HCV infection; an estimated 90% of HIV-infected IDUs are co-infected with HCV. HIV/HCV co-infection in the context of substance abuse is associated with significant morbidity and mortality where pathogenesis of both infections is worsened by the presence of the other. An estimated 1 million people globally and 20,000 in the US die each year from HCV-related cirrhosis and hepatocellular carcinoma. Mortality due to HCV, particularly among those aged 55-64 years, has also been increasing, surpassing that due to HIV for the first time in the US in 2007 (confirmed in 2014). Populations most vulnerable to HIV/HCV co- infection and poor disease outcome are: young (15-24 yr olds) non-urban injectors (started with oxycodone), MSM (1.6/100 person/yrs, [6x more likely); substance users with long-term chronic co-infection and those in incarceration settings. Some of the medical consequences associated with HIV/HCV co-infection of concern are: neuroAIDS, neuropsychiatric complications, cardiomyopathy, HIV-nephropathy, and HCV-renal disease, cardiac and hepatic steatosis; and antiretroviral therapy associated hepatic and cardiac steatosis. Substance abuse itself can exacerbate many of these comorbidities. Although there are several highly effective antiretrovirals (ARTs) available for the treatment of HIV/AIDS and recently approved highly effective direct acting antivirals (DAAs) for HCV cure, access to and successful engagement in treatment for persons with substance use disorders such as IDU and MSM remain critical issues. Therefore, eradication and cessation of viral transmission of infections in dually (HIV/HCV) infected opiate and other drug using populations, IDUs, MSMs, and incarcerated is of paramount importance. Research is needed to develop improved strategies for prevention, screening, linkage to testing and care, and treatment and clinical management of HIV/HCV infection in persons with substance use disorders.
Research questions and areas: The proposed FOA will support studies to show (i) whether HIV/AIDS/HCV disease is negatively impacted by substance abuse and antiretroviral (HIV) and/or drug treatment; (ii) study the impact of HIV and substance abuse on health disparities in accessing care by HIV-infected substance abusing populations; (iii) determine whether drug abuse treatment or reduction in drug use can improve HIV/HCV, and other OIs related health outcomes and/or disease progression; (iv) test efficacy of antiretroviral medications and new HCV DAAs and in HIV/HCV co-infected substance abusers; (v) develop new strategies such as telemedicine for integration of addiction MDs and IDs; (vi) implement adaptations of the STTR strategy to assess impact on care continuum; (vii) assess and prevent re-infections; and (viii) study drug-drug interactions between new ARVs, HAART and addiction medications.
Dr. Jag Khalsa, MS, Ph.D. - Chief, Medical Consequences of Drug Abuse and Co-occurring Infections Branch, Division of Therapeutics and Medical Consequences, NIDA
Between 1999 and 2011, the number of people in pain in the US doubled. Now, nearly one in three Americans suffers from persistent pain. We have a crisis. Partly in an effort to curb this pain, opioid prescribing over has drastically increased. Now we have another crisis, prescription opioid abuse. Over 19,000 Americans died from prescription opioid abuse in 2014. Opioids have too often been used as a replacement for comprehensive pain treatments. Solely relying on opioids for pain is not the answer for people in pain. We need better treatment options for people in pain that is personalized and includes objective measures. Just as we do not rely on a patient’s subjective estimations of core body temperature, blood pressure or heart rate, we should not rely on only subjective measures of pain. This purpose of this RFA is to develop a tool to objectively measure pain for research and treatment purposes. This tool would allow for improve basic and clinical pain research, allow better understanding of biological changes associate with the transition to chronic pain and be used to personalize pain treatment approaches.
David Thomas, Ph.D. - Program Official, Services Research Branch, Division of Epidemiology, Services and Prevention Research (DESPR), NIDA
Currently there are few cost effective tools that enable researchers to study drug addiction relapse and its biological factors in real time. The gold standard in treatment and research settings remains to be urine analysis (UA) or self-report. Unfortunately urine analysis can only detect recent drug use (depending on the type of drug) in the previous 24 to 72h. Many synthetics are not detectable at all.
The proposed SBIR concept will support small business efforts that will address the above mentioned gaps by developing a recovery wearable and supporting mobile applications. Technology feasibility is now possible because of miniaturization and cost reduction of sensors necessary to capture digital biomarkers associated with relapse. However, previous studies included limitations such as lack of ability to capture data in natural environments, the use of proper method of analysis, and data validation. Our proposed wearable will demonstrate that these gaps are addressed. Ultimately, researchers will be able to: Integrate this research tool into substance use disorder treatment services; collect digital biosensor data: breathing patterns, galvanic skin response, and heart rate variability and sleep monitoring; compare bio data can to qualitative assessments and patient self-report; and create a model for just in time interventions.
Samia Noursi - Program Officer, Services Research Branch (SRB), Division of Epidemiology, Services and Prevention Research (DESPR)