$2.7 Million Grant Funds Collaboration to Understand the Role of Protease-Activated Receptor 2 in Chronic Pain Associated with Irritable Bowel Syndrome and Inflammatory Bowel Disease
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH), has awarded Brian Schmidt, DDS, MD, PhD, director of the Bluestone Center for Clinical Research at New York University College of Dentistry (NYU Dentistry) and Nigel Bunnett, PhD, professor in the Departments of Surgery and Pharmacology at Columbia University, a joint $2.7 million, 3.5-year grant to study Protease-Activated Receptor 2 (PAR2) and pain signaling. The study will help determine whether PAR2 can be exploited as a therapeutic target to treat chronic pain.
Chronic pain is a major cause of human suffering that is inadequately treated with current therapies, such as opioids. Schmidt and Bunnett will investigate the role of PAR2 and chronic pain secondary to irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Previously, they collaborated on work that reveals the role of PAR2 in cancer pain, headache, nerve injury pain, and pain secondary to infectious colitis. The PAR2 signaling mechanism is thought to play a role in chronic pain. PAR2 is a specific type of cell surface receptor that is activated by proteases (molecules that sever proteins) located outside the cell. PAR2 activation on neurons produces pain.
Proteases sever a short section of protein that is part of the larger PAR2 structure. This process causes a conformational (shape) change in the receptor which subsequently produces a pain signaling cascade. PAR2 is recycled from the cell surface and internalized in endosomes within a cell. Because the PAR2 conformational change from protease activation is irreversible, signaling from the PAR2 receptor is sustained after it is internalized.
To address the issue of sustained activation, Bunnett developed drugs termed lipidated PAR2 antagonists. These drugs remain bound to PAR2 after internalization and continue to disrupt the signaling mechanism. As a result, drugs that target the endosome are potentially more effective.
Schmidt and Bunnett seek to reveal the PAR2 signaling mechanism by investigating colon pain. IBS and IBD generate proteases that act on PAR2 and cause pain. Schmidt will analyze tissue samples of normal human colon obtained during surgical resection of colon cancer.
“We will use electrophysiologic analysis of nociceptor activation and biophysical imaging to investigate PAR2 signaling from the endosome as well as signaling effects of PAR2 trafficking, or movement of the receptor within the cell,” says Schmidt.
PAR2 is a member of a large family of receptors termed G protein-coupled receptors (GPCRs). GPCRs are the target of one third of all FDA approved drugs. Knowledge gleaned from Schmidt and Bunnett’s work will provide insight into therapeutic targeting of GPCRs within endosomes.
“Ultimately, we seek to confirm the efficacy of the lipidated PAR2 antagonist as a pain medication by targeting receptors in the endosome,” says Bunnett. “However, our work could potentially improve drug efficacy in a broad array of drugs that currently target GPCRs solely on the cell surface.”
The research is funded under NIH/NIDDK grant number R01DK118971.
About the Bluestone Center for Clinical Research
The Bluestone Center for Clinical Research, in conjunction with the NYU Oral Cancer Center, is an academic research organization located at the NYU Dentistry. Bluestone's mission is to take a creative scientific approach to transform world health. Investigators at Bluestone Center conduct research on oral cancer, cancer symptomatology, pharmaceuticals, medical devices, emerging biotechnology, periodontics, implants, and oral health products.
About NYU College of Dentistry
Founded in 1865, New York University College of Dentistry (NYU Dentistry) is the third oldest and the largest dental school in the US, educating nearly 10 percent of all dentists. NYU Dentistry has a significant global reach with a highly diverse student body. Visit http://dental.nyu.edu for more.