Research Interests
Cross-talk between the nervous system and other tissues including organs and immune cells is critical for the regulation of homeostasis as well as the body’s response to trauma, infection, and malignancy. The lab uses a variety of in vitro and in vivo approaches, including anatomical studies, behavior assays, optogenetics, calcium imaging, flow cytometry, immunoassays, and -omics. Collaborations include working with a variety of expert neuroscientists, statisticians/bioinformaticists, geneticists and immunologists as well as clinical oncologists,, surgeons, and gastroenterologists.
Current Research Interests
1. Neural regulation of tumorigenesis, anti-tumor immunity and cancer pain.
2. Autonomic-sensory circuits that regulate pancreas function, pancreatitis and pancreatic pain syndromes.
3. Identification and validation of diagnostic, predictive, and therapeutic biomarkers for pancreatitis and pancreatic pain syndromes.
4. Peripheral nervous system function and nociception
Neurogenic Pancreatitis
Pancreatitis is a debilitating disease characterized by a high incidence of abdominal pain. While it is classically considered an inflammatory disease, over one quarter of patients also exhibit signs and symptoms associated with nerve injury. Less than one third of patients achieve pain relief with currently available analgesics and pain-relieving interventions. Utilizing both classical animal models of pancreatitis as well as a novel optogenetic model of pancreas pain, we are investigating the signaling mechanisms that contribute to these specific sub-types of pain within the context of pancreatic disease. Direct activation of nociceptors using optogenetics enables us to isolate the role of specific neuron subtypes in the absence of mechanical perturbations and injury. Our result suggest that neural activation alone is sufficient to induce acute and persistent pain as well as features of acute pancreatitis. Current studies are investigating the utility of the optogenetic model to induce transition from acute persistent to chronic pain. Future studies will unravel the peripheral circuitry, including communication between autonomic and sensory nerves, involved in regulation of exocrine pancreas function, development and maintenance of pancreatitis and pancreatic pain.
Novel Biomarkers for Chronic Pancreatitis and Pancreas Pain
Currently, there are no diagnostic biomarkers (behavioral, genomic, or proteomic) for early chronic pancreatitis before irreversible morphological changes occur. Furthermore, we know there are many subtypes of pain within the chronic pancreatitis population, but there are very little data to link specific mechanisms with distinct pain presentations. There are also no tools to predict which patients will respond to which pain intervention. In collaboration with NIDDK/NCI sponsored consortia and the Pitt/UPMC clinical research team, we are working to discover and validate potential biomarkers. These studies include animal models of disease, patient biospecimens and patient reported outcomes (e.g. quantitative sensory testing, pain surveys), and -omics analyses to identify potential biomarkers for both diagnosis of chronic pancreatitis as well as specific subtypes of pain.
Human pancreas tumor exhibits close association between intratumoral nerve axons (red) and B and T lymphocytes, (green and yellow, respectively)
Neuro-immune regulation of the tumor microenvironment
There are several ongoing projects investigating mechanisms associated with this neuroplasticity in animal models and human tumor tissues. Clinically, several tumor types are associated with significant sprouting and hypertrophy of peripheral axons resulting in more innervation than that found in the normal healthy organ. The extent of pain and sensorimotor deficits is associated with penetration of the nerves by tumor and immune cells, a phenomenon called perineural invasion. In a genetic model of pancreas cancer, sensory denervation slows or even prevents tumor growth. Ongoing projects are focused on understanding the mechanisms underlying this phenomenon.
Given that the tumor microenvironment often has a significant immune infiltration characterized by a suppressive phenotype, we have expanded this line of investigation to understand how peripheral neurons regulate tumor immune profiles.