Sunday, October 27, 2024
10/27/2024
We lack a complete understanding of the molecular mechanisms that drive the development of the lens fibrotic disease, Posterior Capsule Opacification (PCO) in response to cataract surgery wounding. Our preliminary data indicate a role for mitochondrial remodeling in driving lens fibrosis. Importantly, whether mitochondria play an integral role in the development of PCO is not known. Mitochondria are recognized as central coordinators of cell processes, as not only a major source of ATP for cells, but also through production of metabolites and reactive oxygen species (ROS) that can impact cell signaling. The arrangement of mitochondria within a cell is coordinated by fusion events and by fission to fragment mitochondria into transportable units that can travel along microtubules, an efficient mechanism to provide energy and metabolic needs in a highly localized and specific manner. Our unbiased transcriptome findings with a clinically relevant PCO model, provide strong evidence that fibrosis is associated with gene reprogramming around remodeling mitochondrial function, and metabolic rewiring that favors glycolysis and glutaminolysis. Our findings also support that acquisition to a lens fibrotic phenotype is associated with an increase in mtROS, mitochondrial fission and mitochondrial trafficking along microtubule cytoskeletal elements. Whether PCO development depends on this remodeling of mitochondrial function, including elevated mtROS is not known nor do we know whether PCO development depends on the repositioning of mitochondria within the cell to support the pro-fibrotic phenotype. The objective of this proposal is to deliver new molecular insight into the role of mitochondrial remodeling in driving lens fibrotic disease. The central hypothesis is that mitochondria become remodeled through changes in fission/fusion dynamics and substrate metabolism to drive the acquisition of a pro-fibrotic lens phenotype. The central hypothesis will be evaluated – in a clinically relevant model of PCO, as well as human lens cells and explants derived from human cataract surgery patients - by the following two specific aims: 1) To determine how mitochondrial substrate oxidation impacts mitochondrial ROS production and fibrosis development and 2) To investigate whether modulating mitochondrial fission/fusion dynamics can prevent acquisition to a lens fibrotic phenotype. These aims will be pursued utilizing cutting-edge techniques to investigate mitochondrial bioenergetics and glycolytic flux, a combination of high-resolution confocal microscopy, time-lapse microscopy, and a toolkit of small molecules that specifically target different mechanisms to effect changes in mitochondrial form and function and thus enable mechanistic insights. The proposed research is significant as these studies will provide a new comprehensive understanding about the role of mitochondrial form and function in driving lens fibrosis. The long-term goal is to use this new understanding about mitochondrial remodeling as a foundational resource to create new mitochondrial-targeted treatment strategies for preventing PCO.
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