Jackson Laboratory

Identifying Mechanistic Pathways Underlying Rpe Pathogenesis in Models of Pattern Dystrophy - Project Summary/abstract the Retinal Pigment Epithelium (RPE) Plays an Important Role in the Eye Transporting Nutrients, Ions, and Water; and Serving in Absorption of Light and Protection Against Photooxidation, Recycling of Visual Cycle Components, and Providing Essential Factors for the Structural Integrity of the Retina. Collectively These Support Metabolic Homeostasis and Barrier Function of the Retina. Many Rpe Disease Phenotypes Are Shared Between Humans and Mouse Models Carrying Mutations in Cell- Adhesion and Extracellular Matrix (ECM) Molecules. Defining Causative Pathways and Networks That Are Induced by Mutations or Pathogenic Variants May Provide Therapeutic Targets. Identifying Druggable Targets That Act During the Pre-symptomatic Stage of the Disease Is Particularly Important to Enable Development of Therapies That Can Prevent, Delay Onset, or Decrease the Severity of Rpe-associated Diseases, Irrespective of the Initial Cause of the Disease, Before the Pathologic Changes Become Irreversible. the Goal of This Application Is to Identify Shared Pre-clinical and End-stage Phenotypic and Cellular Effects of Mutations in Two Genes, CTNNA1 and LRATD2, Which Are Highly Expressed in the Rpe and Lead to Similar Retinal Defects. Mutations in CTNNA1 Have Been Reported in Patients With Pattern Dystrophy and Lebers Congenital Amaurosis (lca), and LRATD2 Has Been Associated With Early Amd in a Genome Wide Association Study. Our Approach Is to Use Clinical, Functional and Biochemical Tests to Provide a Deep Characterization of the Models and to Analyze Associated Cellular Changes Using Single-nuclear Transcriptomics as Well as Spatial Metabolomic/proteomic Measurements. These Phenotypic and Genomics Data Will Be Jointly Analyzed Using Computational Methods to Identify the Shared Pathways Perturbed in These Models. Our Use of Two Models With Shared Pathologies Will Let Us Filter Out Mutation Specific Alterations and Focus on the Shared Disease-causing Pathways. Using Our Mouse Resources, We Also Plan to Enhance Current Models. Successful Completion of Our Studies Will Identify Novel Pathogenic Pathways Underlying Rpe-related Disorders, Revealing Potential Therapeutic Targets That Could Be Effective in a Broad Range of These Diseases, Regardless of the Cause of the Disease. These Well-characterized Models Will Be Made Available to the Research Community for Further Mechanistic Inquiries as Well as for Testing Therapeutic Strategies.