Mechanisms of Corneal Neuro-Immune Crosstalk

Tufts Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

Summary The long-term goal of the proposed project is to find a novel diagnostic and treatment approaches that address the corneal hypoesthesia, the hallmark of the neurotrophic keratitis (NK), a vision-threatening condition that results from injury or dysfunction of corneal nerves and subsequent corneal sensory nerve degeneration. The objective of this proposal is to determine the immune cell-type-specific ligand-receptor pairs that are involved in bidirectional cross talk between resident corneal immune cells and sensory afferent nerves originating from the neurons of trigeminal ganglia, and how these interactions impact the sensory afferents in the neurotrophic keratitis (NK). The central hypothesis is that subsets of immune as well as non-immune corneal cell populations play a crucial role in regulating survival and regenerative capacity of corneal sensory afferent neurons via direct neurotrophic support in healthy corneas and that the lack of these neurotrophic factors exacerbate degeneration of TG-derived sensory afferents resulting in progression of NK. The rationale underlying this proposal is that while corneal sensory nerves were shown to promote epithelial and stromal health through secretion of neurotrophic factors and neuropeptides, the target cells, including corneal parenchymal cells and resident and infiltrating leukocytes, also can produce biologically active neurotrophic factors that maintain corneal nerve survival, regeneration and importantly, can impact course of neurodegeneration. The central hypothesis will be tested by pursuing three specific aims: 1) To characterize the cell populations and molecular pathways involved in NK; 2) To identify corneal modulators of diseased nerve function/degeneration in TG-derived sensory afferents in vitro; 3) To assess the role of immune cells in the loss of corneal nerve function/degeneration in NK in vivo. We will pursue our goal using both recently-developed techniques specific to state-of-the art gene expression analysis, the next-generation protein expression analysis, intravital multiphoton microscopy, corneal electrophysiology and more-established techniques that have been uniquely and successfully applied in our laboratory. The expected outcome of this work is a deeper understanding of which neurotrophic molecules and corneal cell populations contribute the most to the positive clinical outcome in the NK. The results will have an important positive impact immediately because they will establish better understanding of complexity of the neuro-immune crosstalk, and long-term because they lay the groundwork to develop cellular-based therapies to promote corneal nerve regeneration for better treatment of NK.