Awarded a one-year, $50,000 grant from Pachyonychia Congenita Project.
Pachyonychia congenita (PC) is one of several inherited skin diseases caused by mutations in keratin genes, which are responsible for forming a scaffold within skin cells that gives the skin strength. PC patients develop symptoms at the body locations where PC keratins are expressed, such as the skin on the palms and soles, at least in part because of localized skin fragility. We are trying to understand if the unique symptoms of PC result simply from the unique expression pattern of PC-keratins or if PC-causing mutations affect skin cells differently from mutations that cause other keratin-related diseases. To do this, we are building a skin organoid model that lets us directly compare different keratins and keratin mutations that are not expressed at the same body location, which may help us find new ways to treat the unique symptoms of PC.
Project Title: Distinguishing mechanical and non-mechanical pathophysiologic mechanisms in pachyonychia congenita
Principal Investigator (PI) Name: Benjamin Nanes, MD, PhD
PI Affiliations: UT Southwestern Medical Center
Abstract
Mutations causing pachyonychia congenita (PC) destabilize the keratin intermediate filament cytoskeleton, which confers mechanical stability to the epidermis. Thus, PC symptoms may be a direct result of epidermal fragility at the anatomic locations where PC-keratins are expressed. However, keratins may have other non-mechanical roles; whether non-canonical PC-keratin functions contribute to distinguishing PC symptoms such as pain and inflammation remains unclear. Because of the overwhelming importance of the keratin filament mechanical scaffold to epidermal stability, distinguishing mechanical and non-mechanical functions of PC-keratins in PC pathophysiology has been challenging and represents a significant obstacle to therapeutic development. We propose to disentangle these functions at the tissue and cellular level. First, we will develop an epidermal organoid model to directly compare the effects of PC causing mutations to those of similar mutations in other keratin isoforms when expressed in equivalent settings. Because the mechanical scaffold function is broadly shared among keratins, any differences in differentiation, barrier
function, or remodeling potential will indicate a non-mechanical contribution of PC-causing mutations to PC pathophysiology. Second, using a proximity biotin labeling approach with bait constructs directed to different subcellular locations, we will identify molecular interactions disrupted by PC-causing mutations independent from disruption of the overall keratin cytoskeletal network. Such interactions could mediate non-mechanical effects of PC-causing mutations and represent potential therapeutic targets. Together, these aims will distinguish specific effects of PC-causing mutations from the general mechanical effects of keratin filament network disruption, and may identify entirely novel treatment strategies.
