GENERATION OF ANIMAL MODELS TO DEFINE MOLECULAR MECHANISMS AND NOVEL THERAPEUTIC STRATEGIES FOR FAMILIAL PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS

The aim of the research

Main researcher PAUL HEPPENSTALL

Familial primary localized cutaneous amyloidosis (PLCA) is a rare skin disease caused by genetic defects in proteins responsible for the actions of an inflammatory molecule called interleukin-31 (IL-31).

Symptoms of familial PLCA include severe itchiness and damage to the skin, both of which are highly distressing and debilitating. Effective treatments for familial PLCA are still to be discovered and understanding the molecular mechanisms of the disease is of primary importance to the development of new therapeutic strategies. The aim of the current proposal is to investigate the mechanisms underlying familial PLCA. We believe that a first step in achieving this is to understand the contribution of different cell types in the skin such as keratinocytes, immune cells and nerve cells to the disease. Once we appreciate how each of these cellular systems influences the disease, we can then tease apart the molecular mechanisms that malfunction and cause the disorder. Finally, using this information, we can design mechanism based therapeutic options to treat familial PLCA. To achieve these aims, we will generate clinically relevant mouse models carrying the genetic defects responsible for the disease. We will validate these models by monitoring scratching behavior and skin histology in mice. We will then establish the contribution of different skin cells to the pathogenesis of familial PLCA by switching on the genetic defects in each cell type. This will allow us to identify the molecular mechanisms that trigger the disease, in particular key cellular pathways correlating with the disease's progress. Finally, we will test novel mechanism based treatment options in our mouse models by targeting these pathways. This study will provide the first mouse models of familial PLCA which will allow a better understanding of its pathology and ultimately the design of new treatment options.