There is a growing body of evidence indicating that peripheral neuron signaling mechanisms contribute to the prognosis, response to therapy, and pain associated with complex disorders such as cancer and chronic inflammatory diseases. Cross-talk between the nervous and immune system is critical for the regulation of homeostasis as well as the body’s response to trauma or infection. Within this context, ongoing projects are focused on: 1) sensory neuron signaling during homeostasis and nerve injury 2) pancreatitis, 3) pancreatic cancer, 4) cancer or treatment related pain, and 5) neuro-immune mechanisms that contribute to pathogenesis. Many of the specific questions addressed in our lab are derived from clinical observations; the lab has ongoing collaborations with clinicians enabling comparative analysis of pre-clinical models and patients.
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
(Clinical Pancreas Research )
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 collaoration with NIDDK/NCI sponsored consortia and the Pitt/UPMC clinical research team, we are evaluating clinical data, patient reported outcomes (e.g. quantitative sensory testing, pain surveys), and biological fluids to identify potential biomarkers for both diagnosis of chronic pancreatitis as well as specific subtypes of pain.
The lab is interested in identification of genomic and transcriptomic biomarkers that inrease risk for chronic severe pain. Toward achieving this goal, we are involved in patient tissue collection and subsequent bulk and single cell sequencing studies to understand the genomic interaction between chronic pancreatitis pain and comorbid mental health issues.
Human pancreas tumor exhibits close association between intratumoral nerve axons (red) and B and T lymphocytes, (green and yellow, respectively)
Click image to enlarge.
Neuro-immune regulation of the tumor microenvironment
(Collaboration with Dr. Vignali, Department of Immunology and Tumor Microenvironment Program)
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. Furthermore, the extent of pain and sensorimotor deficits is associated with penetration of the nerves by tumor and immune cells, a phenomenon called perineural invasion. This study involves investigating mechanisms associated with this neuroplasticity in animal models and human tumor tissues.
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. Furthermore, recent studies have demonstrated that proteins considered to be immune modulators are expressed by sensory neurons. Current studies are designed to determine if neuronal expression of immune proteins directly contributes to the neuronal regulation of tumor growth.