Exposure to gadolinium-based magnetic resonance imaging (MRI) contrast is a major risk factor in the acquisition of nephrogenic systemic fibrosis (NSF), a severely debilitating disease first recognized in patients with acute or chronic renal impairment. MRI contrast agents heretofore were considered safe in these patients and thus indiscriminately used. Gadolinium-based contrast agents remain a mainstay for MR imaging and alternatives are still lacking. The overall objective of this proposal is to identify candidate mechanisms that trigger the aberrant pattern of fibrosis after exposure to gadolinium-based MRI contrast in the setting of renal insufficiency. The central hypothesis is that in the setting of real insufficiency, MRI contrast exposure triggers a pro-fibrotic state in target organs, such as the skin. Subsequent generation of specific chemokines activate and recruit bone marrow-derived and circulating mesenchymal precursor cells, or fibrocytes, to the affected areas. These cells compound the fibrotic process by synthesizing and reducing the generation of extracellular matrix and inducing the proliferation of resident cells. Experiments will address the following Specific Aims. 1a, Determine the mechanism by which gadolinium-based contrast induces NSF. 1b, Demonstrate that gadolinium-based contrast induces an increase in circulating fibrocytes. 2a, Identify the chemokines and receptors responsible for recruitment of bone marrow-derived cells to specific tissues. Resistance to NSF will be examined in animals with a genetic deficiency CCR2. 2b, Test the hypothesis that biodistribution of gadolinium differs between normal renal function and renal insufficiency in mice and rats. The chemical mediators that lead to the recruitment of circulating cells to NSF lesions are not well-explored. The findings will lea to a better understanding of how systemic fibrosis occurs and why certain organs are targeted. These will be applicable to NSF and other fibrocyte-mediated ailments.
Exposure to gadolinium-based magnetic resonance imaging (MRI) contrast is a major risk factor for the acquisition of nephrogenic systemic fibrosis, a severely debilitating disease first recognized in patients with acute or chronic kidney impairment. How the combination of renal insufficiency and MRI contrast leads to organ fibrosis in this disorder is not well-understood, but we have identified that bone marrow-derived cells infiltrate skin using an animal model. This project examines how MRI contrast triggers organ fibrosis, and specific molecular mediators that are promising candidates for a cure.
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