Funded Projects

This International Cooperative Biodiversity Group application aims to discover and develop small molecule drug leads from cultured marine microbes and diverse coral reef organisms collected from Fiji and the Solomon Islands. Drug discovery efforts will focus on four major disease areas of relevance to the United States and low- and middle-income countries: infectious disease, including tuberculosis and drug-resistant pathogens; neglected tropical diseases, including hookworms and roundworms; cancer; and neurodegenerative and central nervous system disorders. Screening in these therapeutic areas will be performed in collaboration with two major pharmaceutical companies, two highly respected academic groups, and various testing centers and government resources that are available to facilitate drug discovery and development. The acquisition of source material for this program will be linked to biotic surveys, informed by ecological investigations addressing the chemical mediation of biotic interactions, and enriched using ecology-based strategies designed to maximize secondary metabolite production and detection.

The Philippine Mollusk Symbiont International Cooperative Biodiversity Group harnesses the vast biodiversity of the Philippines to discover new drugs to treat bacterial infections, parasitic infections, pain, and other neurological conditions and cancer, all of which are serious health problems in both the Philippines and the United States. The Republic of the Philippines represents a unique nexus of exceptional biodiversity, dense human population with pressing societal needs, consequent urgent need for conservation, and government commitment to education and technology to harness national human and natural resources for a sustainable future. Mollusks are one of the most diverse groups of marine animals, and their associated bacteria represent an unexplored trove of chemical diversity. Researchers will use an increasing understanding of the interactions between mollusk symbionts and their hosts to discover the most novel and useful molecules. The project will document and describe Philippine mollusk biodiversity and support training and infrastructure that provide the foundation for conservation of Philippine biodiversity.

The ability to de-risk lead compounds during pre-clinical development with advanced “organoid-on-a-chip” technologies shows promise. Development of microphysiological models of the peripheral nervous system is lagging. The technology described herein allows for 3D growth of high-density axonal fiber tracts, resembling peripheral nerve anatomy. The use of structural and functional analyses should mean drug-induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathology. The goals of this proposal are to establish our human model using relevant physiological measurements in tissues fabricated from human iPS cells and to validate the model system with a library of compounds, comparing against conventional cell culture models. Validating the peripheral nerve model system with drugs known to induce toxicity via a range of mechanisms will demonstrate the ability of the system to predict various classifications of neuropathy, yielding a high-content assay far more informative than traditional in vitro systems.

The research team developed an in vitro multi-component joint on a chip (microJoint), in which engineered osteochondral complexes, synovium, and adipose tissues were integrated. This study will introduce sensory innervation into the microJoint and a neuron-containing microfluidic ally will be developed to innervate the microJoint. The osteoarthritis (OA) model will be created in the Neu-microJoint system. The research team will assess activation and/or sensitization of nociceptive afferents with electrophysiology, as well as neurite outgrowth. They will mechanically insult the Neu-microJoint and assess the emergence of “pain” in response to prolonged mechanical stress. Researchers will assess the impact of drugs used clinically for management of OA on OA models and will then use “omic” approaches to identify new biomarkers and therapeutic targets. Researchers will assess the impact of opioids—which they hypothesize will increase the rate of joint degeneration and potentiate the release of pain-producing mediators—on neural activity in the presence and absence of joint injury, as well as the integrity of all joint elements.

Pain is one of the most common symptoms in cancer patients and one least likely to be adequately treated. It is particularly common in advanced cancer, affecting an estimated 64% of patients with advanced disease. Pain treatment guidelines state patients should have access to behavioral pain interventions that educate them about pain and teach them skills for managing it. The parent grant will evaluate the effectiveness of an evidence based pain management intervention called ?Pain Coping Skills Training? in a web based format for patients with advanced cancer. This supplement will provide support for a training opportunity that aligns with the goals of the parent grant and includes community outreach and engaging underserved populations in clinical research.

Hesperos uses microphysiological systems in combination with functional readouts to establish systems capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. The team constructed physiological systems that represent cardiac, muscle and liver function, and demonstrated a multi-organ functional cardiac/liver module for toxicity studies as well as metabolic activity evaluations. In addition, the team demonstrated multi-organ toxicity in a 4-organ system composed of neuronal, cardiac, liver and muscle components. While much is known about the cells and neural circuitry regulating pain modulation there is limited knowledge regarding the precise mechanism by which peripheral and spinal level antinociceptive drugs function, and no available human-based model reproducing this part of the pain pathway. The ascending pain modulatory pathways provide a well characterized neural architecture for investigating pain regulatory physiology. In this project, the research team propose a human-on-a-chip neuron tri-culture system composed of nociceptive neurons, GABAergic interneurons and glutamatergic dorsal projection neurons (DPN) integrated with a MEMS construct. Using this model, investigators will interrogate pain signaling physiology at three levels, 1) at the site of origin by targeting nociceptive neurons with pain modulating compounds including noxious stimuli and inflammatory mediators, 2) at the inhibitory GABAergic interneuron, and 3) at the ascending spinal level by targeting glutamatergic DPNs. These circuits will be integrated utilizing expertise in patterning neurons as well as integration with BioMEMs devices. This system provides scientists with a better understanding of ascending pain pathway physiology and enable clinicians to consider alternative indications for treating pain at peripheral and spinal levels. 

The clinical utility of opioids for pain treatment is limited by its risk for developing opioid usage disorders (OUD). These untoward effects impose a severe burden on society and present difficult therapeutic challenges for clinicians. We propose to extend our cerebral organoid MPS to facilitate the investigation of neuronal response to opioids and identify cellular and molecular signatures in patients vulnerable to OUD. We have assembled a team with complementary expertise in clinical characterization of OUD, cerebral organoid MPS modeling, single cell RNA-seq technology, and functional characterization of neurons in a mesolimbic reward system to test the hypothesis that midbrain MPS is a clinically relevant pre-clinical model for study of opioid usage disorder.

Mindfulness has been shown to be effective in treating chronic low back pain, but it has not been embedded into routine clinical care. The OPTIMUM study (Optimizing Pain Treatment In Medical settings Using Mindfulness) will address barriers to delivering mindfulness in primary care and determine the effectiveness in this setting. This project extends the stakeholder engagement efforts of the OPTIMUM study by increasing the size and responsibilities of the Community Advisory Board, adding focus groups for participants in both study arms, and collecting stories from study nonparticipants about their experience seeking care for chronic low back pain and their views on participating in research. This expanded effort will optimize recruitment of a diverse and underrepresented sample, maximize retention, and prepare for future implementation and dissemination.

Participants in many clinical trials do not represent the U.S. population. Racial/ethnic minorities are often underrepresented, as are people with lower socioeconomic status and lower education levels, who face additional barriers, such as lack of transportation or childcare. Thus, both recruitment and retention of such populations is challenging, particularly for complementary and integrative health trials. This project proposes to enhance diversity, inclusion, and retention of participants in an ongoing study by creating a patient and caregiver Diversity, Recruitment, and Retention Advisory Board as well as adding a recruitment and retention specialist to coordinate the advisory board and implement necessary activities. The project will also provide evidence-based recruitment tools and will conduct structured interviews with patients who choose not to participate in a study as well as those who are at risk of dropping out to enhance understanding of the barriers and factors contributing to trial recruitment, loss to follow-up, and successful completion.

Pain in the muscles and surrounding connective tissue (myofascial pain) is a significant and poorly understood health concern affecting hundreds of millions of Americans. There is a great need for tools to assess changes to myofascial tissues in individuals with chronic pain as well as to measure the effect of commonly used therapies. This project will use three imaging tools to look at differences between shoulder tissue in people with myofascial pain compared to those without pain. Using a machine learning approach, this research aims to develop a biomarker signature for myofascial pain, which will be evaluated in a randomized controlled clinical trial based on its ability to predict patient responses to myofascial pain treatments.