The fibrotic response is essential for normal wound repair, but it is also the basis for numerous pathologies, many of which occur in the eye. For example, fibrosis is a major complication following trabeculectomy for glaucoma, reversing the improvement in aqueous outflow resulting from surgery. Subcapsular fibrosis in the lens can result in cataracts. Inappropriate fibrosis is central to the proliferative retinopathies, which are devastating diseases. In the cornea, fibrosis creates opacity, and the contraction of fibrotic tissue alters corneal shape. These effects impinge undesirably on the capacity to refract light on the retina, and impact on the outcome of refractive surgery. The long term goal of the proposed project is to improve our understanding of the fibrotic response in the cornea, and to investigate how this response can undertake a more stromal cell expression of collagenase, and enzyme which participates in regenerative remodeling of fibrotic repair tissue once it is deposited. The most significant finding relates to a mechanism for reciprocal interaction between the cell and its extra cellular matrix. It was discovered that such interactions are mediated through an interleukin-1alpha autocrine feedback loop - expression of IL-1alpha is induced, and this collagenase in response to these stimulatory conditions because they are incompetent to activate or sustain the IL-1alpha loop. Based on this observation, the PI has developed a working model in which fibrotic differentiation is under hierarchical regulation and involves progressive acquisition of competencies to respond to environmental signals. The hypothesis driving this proposal is that control of fibrotic program progression determines the regenerative nature of corneal repair. In the next grant period, experiments are proposed to define molecular deficiencies in signaling pathways required for IL-1alpha autocrine loop activity in stromal cells from uninjured cornea. It is further proposed to identify extrinsic/intrinsic factors required for competence to activate the IL-1alpha autocrine loop and for progression of the fibrotic differentiation program. Finally, gene profiles of corneas repairing by fibrosis and corneas repairing via a more regenerative response - cell replacement - will be compared. The results of our proposed studies should elucidate mechanisms controlling fibrotic program progression and provide some of the essential rationale for developing new therapeutic approaches applicable to improving outcomes of corneal surgeries. These results may also be generally applicable to strategies for managing fibrotic pathologies in other parts of the eye.
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