Funded Projects

NOFO Title: Developing Regulated Therapeutic and Diagnostic Solutions for Patients Affected by Opioid and/or Stimulants use Disorders (OUD/StUD) (R43/R44 - Clinical Trial Optional)
NOFO Number: RFA-DA-23-021
Summary:

Hospitalized patients often receive opioids for pain and sleep management, which can contribute to opioid dependence and continued use after leaving the hospital. Even when hospital stays are extended to wean people from opioids, these patients remain at increased risk for opioid use disorder and withdrawal.  This project will develop a novel small molecule medication that blocks nerve inflammation to prevent opioid dependence in hospitalized patients receiving opioids. 

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed)
NOFO Number: PA-18-575
Summary:

 Chronic persistent post-operative pain (CPOP) is a devastating outcome from any type of surgical procedure. Its incidence is anywhere between 20-85% depending on the type of surgery, with thoracotomies showing one of the highest annual incidences of 30-60%. Given that millions of patients (approximately 23 million yearly based on incidence) are affected by CPOP, the results are increased direct medical costs, increased indirect medical costs due to decreased productivity, and associated negative effects on an individual’s physical functioning, psychological state, and quality of life. Given these extensive public health and economic consequences there is a resurgence of research in the area of preventative analgesia.  The goal of this project is to evaluate a novel small molecule antagonist of MD2-TLR4, DT-001 in preclinical models of surgical pain representative of persistent post-operative pain. In collaboration with University of California, San Diego, DT-001 will be evaluated for its ability to block the development of neuropathic pain states. These studies will evaluate dose escalating efficacy of DT001 in rats in formalin and spinal nerve injury (SNI) models using both intrathecal and intravenous routes of administration. Tissues will be preserved to assess functional effects on relevant pain centers for analysis by Raft. With demonstration of efficacy, these studies will determine the optimal dose and route of administration of DT001 and guide a development path to IND and eventually clinical trials.

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
NOFO Number: PA-18-574
Summary:

Voltage-gated sodium channels are responsible for the transmission of pain signals. Nine genes have been identified, each having unique properties and tissue distribution patterns. Genetic studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform – ?Na?V?1.7 – with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP are not able to feel pain without any significant secondary alteration. Thus, selective inhibition of ?Na?V?1.7 in normal humans could recapitulate the phenotype of CIP. This research team developed a non-permanent gene therapy to target pain that is non-addictive (because it targets a non-opioid pathway), highly specific (only targeting the gene of interest), and long-term lasting (around 3 weeks in preliminary assays in mice). During this Phase I , the team will 1) test additional pain targets ?in vitro?, and 2) evaluate the new targets ?in vivo ?in mice models of inflammatory and neuropathic pain. 

NOFO Title: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-21-010

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

MCAM is a novel opioid antagonist that can be used for opioid overdose reversal and has advantages over naloxone, including a pseudo-irreversible interaction with the ?-opioid receptor and a longer duration of action. Studies in animal models demonstrate MCAM’s long duration of action against the reinforcing and respiratory-depressant effects of remifentanil and heroin, indicating that could be a better treatment option for opioid use disorder. This project studies the pharmacodynamics of MCAM through animal toxicity and safety studies to establish the necessary and sufficient conditions from which to establish MCAM’s safety and antagonist activity in animals and humans. MCAM may be able to prevent all actions of any ?-receptor opioid drug in humans for a longer period of time than any other antagonist given acutely.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this research. This research will focus on three different channels critical to nervous function. One is the"M-type" (KCNQ, Kv7) K+ channel that plays fundamental roles in the regulation of excitability in nerve and muscle. It is thought to associate with Gq/11- coupled receptors, protein kinases, calcineurin (CaN), calmodulin (CaM) and phosphoinositides via AKAP79/150. Another channel of focus is TRPV1, a nociceptive channel in sensory neurons that is also thought to be regulated by signaling proteins recruited by AKAP79/150. The third are L-type Ca2+ (CaV1.2) channels that are critical to synaptic plasticity, gene regulation and neuronal firing. This research will probe complexes containing AKAP79/150 and these three channels using"super-resolution" STORM imaging of primary sensory neurons and heterologously-expressed tissue-culture cells, in which individual complexes can be visualized at 10-20 nm resolution with visible light, breaking the diffraction barrier of physics. The researchers hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which the researchers will examine by patch-clamp electrophysiology of the neurons. Förster resonance energy transfer (FRET) will also be performed under total internal reflection fluorescence (TIRF) or confocal microscopy, further testing for complexes containing KCNQ, TRPV1 and CaV1.2 channels. Since all three of these channels bind to AKAP79/150, the researchers hypothesize that they co-assemble into complexes in neurons, together with certain G protein-coupled receptors. Furthermore, the researchers hypothesize these complexes to not be static, but rather to be dynamically regulated by other cellular signals, which the researchers will examine using rapid activation of kinases or phosphatases. Several types of mouse colonies of genetically altered AKAP150 knock-out or knock-in mice will be utilized.

NOFO Title: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
NOFO Number: PA-18-484
Summary:

Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects, including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small amounts of an opioid to treat pain, thereby lowering the risk associated with larger doses. Unfortunately, very little is known about interactions between 5-HT2 receptor agonists and other opioids. The proposed studies will evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-reinforcing (leading to misuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. If successful, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.

NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for PA-18-906 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-023
Summary:

Chronic orofacial pain during Temporomandibular Disorders (TMD) and oral cancer is a significant health problem with scarce non-opioid treatment options. This study aims to validate critical regulators of the balance between protective immunity and immunopathology during chronic inflammatory diseases?tumor necrosis factor alpha superfamily members, LIGHT (TNFSF14) and lymphotoxin-beta (LT?) and their receptors, LT?R and Herpes Virus Entry Mediator (HVEM)?as novel therapeutic targets. The study also seeks to determine whether inhibition of LIGHT and LT? signaling prevents the development and inhibits maintenance of chronic TMD and oral cancer pain via peripheral mechanisms involving plasticity of immune, muscle and tumor cells as well as sensory neurons. The study will define the contribution of LIGHT and LT? signaling to TMD-induced excitability of trigeminal sensory neurons innervating the masseter muscle and joint. New validated therapeutic targets for prevention and treatment of orofacial pain that can be peripherally targeted would reduce side effects of current pain medicates related to drug dependence or tolerance.

NOFO Title: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
NOFO Number: PA-18-484
Summary:

Deaths from opioid overdose continue to rise; from 2015 to 2016, there was a 28 percent increase in the number of fatal overdoses. Currently available pharmacotherapies include MOR agonists (e.g., buprenorphine) and antagonists (e.g., naloxone), all of which suffer from specific and clear limitations. To address the main deficits in these treatments, the researchers will develop and optimize medications with longer duration of action that prevent and reverse the effects of opioids in a manner that is not surmounted by increasing doses of agonist. Their pilot studies in monkeys show that the pseudo irreversible MOR selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses—as well as protects against—respiratory depression by heroin, with a single injection being effective for a week or longer. Bringing a medication like this to marketable fruition could significantly improve the treatment of OUD and save lives by providing insurmountable extended protection after rescue from overdose, including from ultra-potent fentanyl analogs.

NOFO Title: Career Development Awards in Implementation Science for Substance Use Prevention and Treatment (K01 - Clinical Trial Required) 
NOFO Number: PAS-22-206
Summary:

Many people with opioid use disorder (OUD) also have a serious mental illness and other chronic conditions, which can be difficult for individuals and primary care providers to manage. A chronic disease self-management program is an established health care model in which peers help to educate patients about their condition(s) and build problem-solving skills to manage their health. Such programs have been effective in other populations and settings, but they have not been adapted for primary care patients who have OUD and SMI. This project will adapt and test a chronic disease self-management program for this population to understand its feasibility, acceptability, impact, and how best to put such programs into place widely in primary care settings.

NOFO Title: Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R33)
NOFO Number: RFA-AT-16-006
Summary:

Low back pain (LBP) is a common and costly condition. Spinal manipulative therapy (SMT) is a common mind-body intervention for individuals with LBP. Studies that have supported SMT have generally found relatively small treatment effects. The prior work of this research team has identified two mechanisms explaining the therapeutic effects of SMT: a reduction in spinal stiffness and improved activation of the lumbar multifidus muscle. Our research team has also developed accurate, non-invasive methods to measure these effects and their response to SMT. Our overall goal is to optimize SMT treatment protocols for patients with LBP. In this project, we will use innovative methodology to efficiently evaluate the effects of various individual treatment components toward an overall effect. Results of this project will provide optimized SMT protocols that will be ready for application in future randomized controlled trials examining the efficacy and effectiveness of SMT.

NOFO Title: HEAL Initiative: Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) (UG3/UH3, Clinical Trials Optional)
NOFO Number: RFA-AT-20-004
Summary:

Back pain is the most common chronic pain diagnosis and the most common diagnosis for which opioids are prescribed. Clinical practice guidelines make it clear that nonpharmacologic treatments are preferable to opioids for patients with back pain. Despite clear evidence, over-prescribing of opioids to individuals with back pain continues. Providers of nonpharmacologic care are often absent or unreachable from rural and low-income communities and patients with limited financial resources. Many rural and low-income communities are served by Federally Qualified Health Centers (FQHCs) that are at the forefront of the opioid crisis, but often lack adequate options to provide accessible nonpharmacologic treatments. This pragmatic clinical trial will compare the effectiveness of different telehealth strategies to provide effective nonpharmacologic interventions to overcome the barriers specific to serving rural and low-income communities. The trial will evaluate two strategies, one providing both a brief pain teleconsult with phone-based physical therapy, the other uses an adaptive strategy ? providing the brief pain teleconsult first, followed by phone-based physical therapy to those who need additional treatment. The study will also evaluate outcomes related to the efforts to implement strategies in FQHC clinics. This research will provide a toolkit for future efforts to make nonpharmacological interventions for back pain available in other low resource health care settings.