Collagen is continuously degraded and remodeled as well as produced in both health and fibrotic disease. Our laboratory has demonstrated that the intracellular pathway of collagen uptake and degradation is tightly regulated. In mouse models, the intracellular pathways of collagen degradation have been shown to be important in modulating pulmonary fibrosis. However, the specific mechanisms that regulate collagen internalization and degradation in cells remain incompletely elucidated. Currently, there are no therapies that target these pathways to modulate and augment degradation of fibrotic tissue even though this would have a significant impact on patients with established fibrotic disease. Our laboratory previously published an RNAi- based screen of drosophila phagocytes that identified promising candidate genes that may regulate collagen uptake in mammals including Cell division cycle 7 (CDC7) kinase. The knockdown of this gene led to increased collagen uptake in multiple in vitro systems and this also corresponded with increased expression of a canonical collagen endocytic receptor. These findings raise the interesting possibility that regulatory mechanisms exist that inhibit collagen degradation and these could be exploited to treat fibrosis. Based on these findings, the proposed studies are designed to explore (1) how CDC7 regulates collagen endocytic machinery and (2) whether inhibition of the CDC7 pathway regulates collagen turnover in vivo both at the cellular level and in accelerating the resolution of experimental fibrosis in a well-established murine model. We anticipate that these experiments will expand our understanding of matrix biology and provide the foundation for the design of therapies that could treat human disease.
Idiopathic Pulmonary Fibrosis is a relatively common disorder of progressive scarring in the lungs that is almost uniformly fatal. In some specific instances of pulmonary fibrosis, lung scarring can improve but we do not understand precisely how this happens. The research described in this proposal seeks to understand how scarring may be reversed in Idiopathic Pulmonary Fibrosis with the hope of ultimately taking advantage of these mechanisms to treat this disease.
