Hedgehog Pathway in Chronic Pancreatitis
Abstract
Fiscal Year 2022 Peer Reviewed Medical Research Program Topic Area: Pancreatitis Pancreatitis is an inflammatory disease of the pancreas that results in significant morbidity, mortality, and hospitalizations. A single bout of pancreatic injury induces acute pancreatitis. Fortunately, the pancreas has the potential to recover from this injury and regain its normal form and function. However, ongoing injury to pancreas, e.g., ongoing alcohol abuse, results in continued inflammation of the pancreas and damage to the pancreatic tissue. This leads to a healing response that results in excessive fibrosis akin to a chronic wound. Unlike in acute pancreatitis (AP), for unknown reasons, the pancreas is not able to recover and gain normal form and function once chronic pancreatitis (CP) sets in. Chronic pancreatitis results in insufficient pancreatic function, i.e., insufficient digestive enzymes as well as insufficient insulin production, leading to diabetes. Patients with chronic pancreatitis also have unbearable pain, which can lead to spiral of drug abuse and alcoholism with accompanying social and economic consequences. Unfortunately, due to high prevalence of the etiologic factors including alcoholism, smoking, and drug abuse, our military personnel and Veteran population bear significant brunt of this disease. Despite the evident need, owing to our incomplete understanding of the pathophysiology of the disease, there is no specific therapy for CP. In our preliminary studies, we have observed that the Hedgehog pathway, an evolutionarily conserved signaling pathway, is overactive in animal models as well as in human CP specimens. Furthermore, in our preliminary studies, inhibition of Hh pathway by drugs led to marked improvement in outcomes of chronic pancreatitis. These results are very promising as these suggest that Hh pathway inhibition could emerge as novel therapy for the treatment of CP, a disease for which no treatment is current available. The overarching goal of the proposed studies is to develop preclinical data that will support a clinical trial of Hh inhibition for the treatment of CP, and for preventing development of CP in patients who have recurrent attacks of AP in near future. These studies have high translational value as multiple drugs to inhibit Hh are in clinical use for non-pancreatic indications, for instance, for treatment of basal cell cancer and leukemia. These drugs also have been shown to be fairly tolerable. Our proposed studies will also elucidate the mechanism by which Hh pathway activation leads to worse outcomes in CP. Specifically, we will evaluate the effect of Hh pathway activation on pancreatic stellate cells, which are resident cells of pancreas and are known to orchestrate pancreatic fibrosis and injury in CP. Furthermore, we will elucidate how Hh pathway affect immune response in CP leading to further worsening of CP outcomes. As part of the current project, we are also analyzing over 100 pancreas specimens obtained from patients who have undergone surgery for CP. This is unique as such a large number of CP pancreas specimens have never been evaluated before. This will generate data that will not only help us study our area of interest but will be of benefit to current and future researchers who are trying to find novel therapies for CP. Thus, in short term, these studies will lead to development of inhibition of Hh pathway as novel therapy for the treatment of CP. In the long term, these studies will help us understand the pathogenesis of CP, which lead to development of additional drugs. This together will help improve the outcomes of our military personnel and civilians suffering from CP.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310307
Entities
People
- Melena D Bellin
Organizations
- United States Army
- University of Minnesota