Pulmonary fibrosis is a process in which fibrotic lesions form in the lung resulting in scarring and an irreversible decrease in oxygen diffusion capacity. This type of tissue damage is the endpoint of many disorders of the lung. Of the known conditions involving lung fibrosis, Idiopathic Pulmonary Fibrosis (IPF) is considered the archetype. IPF is a progressive and fatal lung disease of unknown cause. Current estimates of disease incidence are 40-50 per 100,000 and approximately 125,000 cases in the United States. The overall lack of a clear understanding of the disease pathology makes it difficult to diagnose the condition, to predict disease course and similarly difficult to devise new methods to treat the disease. While there are currently no truly effective methods to treat IPF, there is recent strong evidence to suggest that immune cells such as monocytes and macrophages play important roles in the overall disease pathology and some recent therapeutic strategies have focused on immune-modulatory agents. For these reasons, new imaging agents that can be used to specifically image macrophage function in the lung may have broad value in early detection as well as in disease and therapy monitoring in a broad range of conditions involving lung fibrosis. This proposal outlines plans to develop a novel class of small molecule probes that specifically report on the activity of cysteine proteases in activated immune cells using non-invasive imaging methods. Because these probes can be administered directly to the lung and bind only to the activated form of the protease target, they specifically report on areas of 'activ disease'. Such imaging agents will allow systematic monitoring of both disease progress and response to therapeutic agents. Furthermore, such diagnostic agents will allow rapid identification of high-risk patient populations that could be more aggressively treated. Such stratification of the patient population would also ultimately lead to a better understanding of th heterogeneity of the disease and aid in future design of therapeutic strategies.
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung, which is ultimately fatal in the majority of those afflicted. This project outlines plans to identify novel small molecule imaging probes that can be used to non-invasively monitor IPF disease progression as well as response to therapeutic agents designed to reduce fibrosis in the lung. Ultimately, this approach could lead to a better understanding of IPF, which could lead to methods for earlier diagnosis as well as novel therapeutic approaches. (End of Abstract)
|Withana, Nimali P; Garland, Megan; Verdoes, Martijn et al. (2016) Labeling of active proteases in fresh-frozen tissues by topical application of quenched activity-based probes. Nat Protoc 11:184-91|
|Ofori, Leslie O; Withana, Nimali P; Prestwood, Tyler R et al. (2015) Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery. ACS Chem Biol 10:1977-88|
|Oresic Bender, Kristina; Ofori, Leslie; van der Linden, Wouter A et al. (2015) Design of a highly selective quenched activity-based probe and its application in dual color imaging studies of cathepsin S activity localization. J Am Chem Soc 137:4771-7|
|Verdoes, Martijn; Oresic Bender, Kristina; Segal, Ehud et al. (2013) Improved quenched fluorescent probe for imaging of cysteine cathepsin activity. J Am Chem Soc 135:14726-30|
|Lee, Jiyoun; Bogyo, Matthew (2013) Target deconvolution techniques in modern phenotypic profiling. Curr Opin Chem Biol 17:118-26|
|Puri, Aaron W; Bogyo, Matthew (2013) Applications of small molecule probes in dissecting mechanisms of bacterial virulence and host responses. Biochemistry 52:5985-96|