RAGE in pulmonary fibrosis

Description of projects available to graduate students:
The receptor for advanced glycation endproducts (RAGE) has been studied extensively in diabetic vascular disease. Ligation of this receptor with advanced glycation endproducts (AGEs), which are produced in excess in diabetics due to high glucose levels, leads to inflammatory responses that contribute to both renal and vascular diseases. Notably, a soluble varient of RAGE (sRAGE) which lacks the transmembrane domain and is secreted, acts as a decoy receptor and prevents vascular disease in mouse models of diabetes.

Notably, AGEs have been shown to be increased in patients with idiopathic pulmonary fibrosis. Furthermore, the lung contains very high levels of sRAGE which we have hypothesized acts to inhibit inflammatory reactions in the lung. We have purified, characterized and cloned mouse soluble RAGE and produced several antibodies to total and membrane RAGE and are currently generating transgenic mice to overexpress sRAGE in the lung.

On this rotation, the student will utilize the above tools to test the hypothesis that RAGE signaling contributes to injury in mouse models of pulmonary fibrosis and that these injuries can be prevented with sRAGE. The models currently examined include a model of bleomycin-induced pulmonary fibrosis and a model of asbestos-induced pulmonary fibrosis (this later model provides great opportunities to obtain funding from NIEHS who have several pre-doctoral awards available for PhD and MD-PhD students).

We have recently discovered that RAGE has important, but different effects on pulmonary fibrosis depending on the model examined. New projects will evaluate why there are differences in the role of RAGE in the different models and determine which models are best predictive of how RAGE will contribute to human idiopathic pulmonary fibrosis.

NOTE: RAGE signaling has also been implicated in neurodegnerative diseases such as Alzheimer's Disease. Students interested in models of neurodegeneration can participate in a rotation with Dr. Oury and Dr. Charleen Chu to undertake studies pertaining to RAGE/sRAGE in models of neurodegeneration.

Techniques graduate student will learn:
Transgenic mouse models of pulmonary fibrosis. Recombinant protein expression and purification. Western blotting. Real time quantitative RT-PCR. Biochemical measurements of pulmoanary fibrosis and inflammation including HPLC and FPLC. Immunochemical and confocal immunoflourescent studies. Pathologic assessment of lung injury.