Laying the Foundation for the NYU Pain Research Center: Current Research
Our Researchers Discuss Their Work
In recent years, a growing number of NYU Dentistry researchers have been working to develop non-opioid therapies for the treatment of chronic pain. Synopses of their research appear below.
Donna Albertson, PhD, is professor of oral and maxillofacial surgery. Her research portfolio includes studies in the areas of molecular cytogenetics, neuroanatomy, and cancer using the model organism Caenorhabditis elegans, mice, and human patients. Dr. Albertson was a pioneer in the development and applications of fluorescent in situ hybridization and microarray technology. She holds patents in microarray hybridization, printing and imaging technology, and cancer biomarkers.
According to Dr. Albertson, “Pain is evoked by mediators released from the tumor and surrounding cells that make up the tumor microenvironment, including fibroblasts and cells of the vasculature and immune systems. The mediators activate nearby sensory nerves. In turn, neurons and other cells of the microenvironment provide support for the growth and spreading of the tumor cells. We are investigating the reciprocal interactions between cancers and the microenvironment for their roles in the generation of pain and promotion of cancer growth and metastasis. We find that pain mediators are released from cancer cells in extracellular vesicles shed by the cancers. The vesicles carry proteins, lipids, and small ribonucleic acids. The vesicles and their contents interact with and modify behavior of other cells in the microenvironment. We identified small RNAs with potential to modulate neuronal activity and pain that were enriched in the extracellular vesicles carried by cancer cells. These studies add RNAs to the repertoire of identified protein and lipid oral cancer pain mediators. The combinations of these mediators in different proportions in different cells and cancers reflect the heterogeneity of cancers and likely contribute to the patient-specific nature of oral cancer pain.”
Bradley Aouizerat, MS, PhD, is professor of oral and maxillofacial surgery and deputy director of the NYU Dentistry Translational Research Center. Dr. Aouizerat’s research focuses on the discovery and characterization of genetic and epigenetic determinants of common symptoms experienced in chronic diseases. These include pain, fatigue, sleep disturbance, and depressive symptoms. The role of pharmacogenomics in the treatment of chronic disease and risk for common symptoms is also a research focus.
“Our group focuses on pain experienced by two populations of individuals,” says Dr. Aouizerat, “those living with chronic HIV infection and those who are being treated for their cancer or who are in remission (often referred to as cancer survivors). Our interest is in identifying genes and biological processes that are disordered in those who experience pain. We also examine how disease severity worsens pain severity and how the “wear and tear” of disease management may accelerate biological aging.
"The goal of our work is to identify new treatment targets for pain that do not rely on opioids. We employ data-intensive approaches to examine the genomes of biological samples collected from research participants enrolled in our studies. We value a multidisciplinary approach, and our network of investigators spans the disciplines of molecular epidemiology, biology, nursing science, basic science, biostatistics, and epidemiology, several of whom are located at the NYU College of Dentistry and the NYU Meyers College of Nursing.”
Aditi Bhattacharya, BDS, MDS, PhD, an assistant professor of oral and maxillofacial surgery, is an oral pathologist-scientist at the Translational Research Center and the NYU Oral Cancer Center. Oral cancer patients suffer severe and intractable pain. The Bhattacharya laboratory aims to better understand the three-dimensional relationships of oral cancer cells with the surrounding cancer-microenvironment, i.e., the nerves, blood vessels, fibroblasts, collagen fibers and immune cells that surround the cancer. Signaling between the cancer and its microenvironment results in pain. Understanding and disrupting these signals is therefore critical for discovering effective pain-medications for oral cancer patients.
“In past studies of oral cancer patient cohorts,” says Dr. Bhattacharya, “my team and I showed that patients with metastatic cancer experience greater pain than those with non-metastatic cancer. Patient-reported pain predicted metastasis prior to surgery, with low pain scores predicting low metastatic risk similar to tumor depth, the current diagnostic standard for predicting metastasis. I have also shown that cancer architecture (seen under a microscope) is related to cancer pain in human samples and preclinical models.”
The Bhattacharya laboratory takes a multifaceted approach to further examine the relationship of oral cancer pain and metastasis. Forty cancer-related genes were overexpressed in painful and metastatic cancers. The role(s) of these genes in cancer pain is unknown. “I study the interactions between these genes, ion channels (present on cancers and nerves), and the cancer-microenvironment in the causation of oral cancer pain,” says Dr. Bhattacharya. “My program — funded by the National Institute of Dental and Craniofacial Research – spans clinical studies in patients, microscopic study of pathological specimens, and preclinical models of oral cancer and pain.”
Dane Jensen, PhD, assistant professor of molecular pathobiology, is a basic research scientist investigating the signaling mechanisms of G protein-coupled receptors in itch, pain, and inflammation.
“Chronic itch is a major unmet medical problem with one in four adults experiencing chronic itch in their lifetime,” says Dr. Jensen. “Chronic itch impairs the quality of life of those who suffer and unfortunately we have very few effective treatments for itch.”
My lab focuses on a family of receptors called G protein-coupled receptors (GPCRs) that are involved in itch sensation in the skin and in the transmission of itch to the central nervous system. GPCRs are very dynamic proteins, and my lab is involved in understanding how these receptors are activated by substances in the environment that contact skin and cause itch. We are also investigating how the activation of itch sensory neurons in the skin leads to activation of neurons in the spinal cord. GPCRs play a pivotal role at each step in the itch pathway, from the sensation in the skin to the excitation of neurons in the central nervous system. We believe that by understanding which neuronal targets are activated, we can develop a road map of the sensory pathway that controls itch. In addition, by investigating how and where GPCRs signal in these itch neurons, we can develop new treatments to inhibit the itch sensory pathway and provide effective relief for a large population of people suffering from chronic itch.
Seiichi Yamano, DDS, PhD, DMD, MMSc, associate professor of prosthodontics, is a clinician (prosthodontist)/scientist. He directs a research program focused on gene delivery, especially non-viral vectors for the management of disease-related symptoms. Dr. Yamano has a broad background in immunology, microbiology, and molecular biology with specific training and expertise in gene therapy research undertaken at NIH (viral delivery) and Harvard (non-viral delivery).
According to Dr. Yamano, “Over the past 15 years, the Yamano laboratory has developed three novel non-viral hybrid vectors for the delivery of genes into the cancer microenvironment: 1) a cell-permeable peptide; 2) a polymer for DNA delivery; and 3) the peptide combined with a lipid and a polymer for RNA delivery. These non-viral vectors have high transfection efficiency with little toxicity in a range of cell lines including cancer cells. Dr. Schmidt’s group and Dr. Yamano’s laboratory have collaboratively investigated treatment modalities for oral cancer pain. Dr. Schmidt showed that OPRM1 (the gene for the µ-opioid receptor, an important factor in controlling pain) is downregulated in oral cancer compared to matched normal tissues in the same patients. In addition, protease-activated receptor-2 (PAR2) is elevated on neurons that innervate the cancer, which contributes to cancer pain. To address the varied pain producing pathways that signal cancer pain, Drs. Schmidt and Yamano have been trying to re-express OPRM1 and downregulate F2RL1 (the gene for PAR2) with the non-viral vectors in the cancer to eliminate cancer pain. The long-term goal is to completely reverse cancer pain and restore oral function, which would allow patients to talk, eat, and drink comfortably.”
Ye Yi, PhD, MS, MBA, is assistant professor of oral and maxillofacial surgery and of molecular pathobiology and associate director for clinical research operations in the Translational Research Center. Dr. Ye seeks to understand the neurobiological basis of oral cancer pain. The long-term goal of her research is to develop novel therapies that target mechanisms common to both tumor progression and cancer pain.
“There is a huge unmet need in treating cancer pain,” says Dr. Yi. “There are currently no approved non-opioid treatments for patients who suffer from severe cancer pain. Among all cancers, oral cancer is one of the most painful and debilitating. The basic neurobiology of cancer pain is poorly understood.
“We use data from patients to guide our pre-clinical models, and use evidence gained from preclinical models to screen for drug targets that are novel, mechanism-based, and target specific. We study pain as one of the disorders that is caused by complex, maladaptive molecular and cellular events. The goal is to trace the central modulator for such maladaptation so that we can possibly treat pain together with other related comorbidities. We use a variety of techniques including cell culture, preclinical modeling, live cell imaging, pharmacology, and electrophysiology to study the dynamic interaction between peripheral nerves and cells within the tumor microenvironment.”