Cholangiocytes are the target cells in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). During the course of these diseases, mitotically dormant cholangiocytes are stimulated to proliferate and then are damaged. Associated with these cholangiopathies is a dysregulation of various neuroendocrine factors derived from the hypothalamus and the acquisition of a neuroendocrine phenotype in cholangiocytes. Taken together, these events contribute to the autocrine and paracrine pathways that modulate the proliferative response of cholangiocytes as well as liver damage and fibrosis in cholestatic liver injury. We have previously shown that circulating neuropeptide Y, and corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have recently demonstrated that the hypothalamic-pituitary-adrenal axis is dampened resulting in suppressed glucocorticoid levels during extrahepatic biliary obstruction and that reactivation of the HPA axis by hypothalamic administration of CRH suppresses the proliferative capacity of cholangiocytes after bile duct ligation (BDL), suggesting a broader concept of hypothalamic control of cholangiocyte proliferation. The objective of this proposal is to investigate mechanisms by which cholestasis regulates the expression of the hypothalamic peptide galanin and the subsequent effects of this altered response on cholangiocyte proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that the bile acids that accumulate in the serum during cholestasis are responsible for the increased hypothalamic and circulating galanin levels and that the central and peripheral effects of galanin co-ordinately regulate cholangiocyte proliferation. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (1) The expression of the hypothalamic peptide galanin is upregulated during cholestatic liver diseases and activates the growth hormone releasing hormone (GHRH) /growth hormone (GH) axis to induce cholangiocyte proliferation, (2) Circulating levels of galanin are increased during experimental cholestasis and can act on cholangiocytes directly to induce proliferation, and (3) The alteration of the galanin expression in the hypothalamus is a direct result of the actions of bile acids in th hypothalamus. Dissecting the pathophysiological interactions between the brain and the liver during cholestatic liver diseases may lead to an enhanced understanding of the pathological processes and consequences of this particular type of live disease. This knowledge may play a paramount role in the development of therapeutic strategies for the treatment of cholangiopathies.
The research program proposed herein is significantly relevant to the VA mission and its successful completion will likely benefit Veteran patients. The risk of liver diseases due to alcohol and toxin abuse in US Veterans is increasingly high and is one of the most common reasons for hospitalization, morbidity and mortality in US Veterans. Scientific interest in cholangiocytes (cells lining the biliary tract) is due to the fact that these cells are the target ells in cholangiopathies or diseases like primary biliary cirrhosis. Management of cholangiopathies (characterized by cholangiocyte proliferation or damage) represents one of the major challenges for the VA. These diseases are often associated with an impaired brain function that leads to dysregulated hypothalamic neuropeptide control. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase the opportunities for the development of novel treatment paradigms for chronic liver diseases.
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