The long-term goal of the Strong laboratory is to understand the morphogenesis and homeostasis of functional tissue barriers. Perturbations in this complex biological process often lead to inflammation and opportunistic infections. We use the mammalian skin as a model system to explore the molecular mechanisms governing protective barrier formation. These investigations will enable us to understand how these mechanisms are perturbed in common skin diseases.
The Epidermal Differentiation Complex locus (EDC) encodes many proteins that are cross-linked together to form one of the essential components of the skin epidermal barrier. To date, very little is known about the molecular mechanisms to regulate the EDC. How are genes in the EDC coordinated? On a genomic scale, how does a proliferating epidermal cell evolve to a terminally differentiated cell and form the essential unit of the skin barrier? Why is the EDC genetically implicated in common inflammatory skin diseases, atopic dermatitis and psoriasis, that are barrier-impaired? What are the genetic variants in the EDC in these diseases? How do they contribute to the pathophysiology? We are currently addressing these basic science and translational research questions using experimental and computational approaches in mice and men.
We have previously identified a group of conserved noncoding elements (CNEs) in the EDC that demonstrate dynamic regulatory activity. Two CNEs, 621 and 923, exhibited epidermal-specific enhancer activity in transgenic reporter mice. CNE 621 mapped within a psoriasis copy number variant (LCE3C_LCE3Bdel) suggesting loss of regulatory activity in psoriasis. We are currently investigating a role for CNE923 as a locus control region (LCR) or “master switch” for EDC gene expression using experimental (molecular, biochemical) and bioinformatic approaches.
How does a proliferating epidermal cell (keratinocyte) evolve to a terminally differentiated cell and form the essential unit of the skin barrier? We hypothesize that execution of this biological process relies on the epigenome of the keratinocyte. To address this, we are capturing global epigenetic changes in the different physiological states of the keratinocyte using ChIP-Seq and RNA-Seq coupled with next-generation sequencing.
Several genetic variants have been identified in the common inflammatory skin disease, atopic dermatitis, including the gene filaggrin, FLG, in the EDC. Linkage to the EDC still persists while excluding FLG. This observation and identification of a tagging SNP on 11q13 suggest additional genetic variants in AD. We hypothesize that causal variants reside near these tagging SNPs. We are currently investigating additional variants using targeted deep-sequencing using case-control studies in pediatric atopy.
Chronic itch or pruritis that lasts more than 6 weeks is one of the most challenging diseases to manage in the clinic. Current anti-pruritic treatments are largely ineffective and this is a reflection of our lack of understanding of the pathophysiology of itch. To date, very little is known about the epicutaneous, molecular markers associated with chronic itch severity in humans. The tight comorbidity of chronic itch to common inflammatory skin diseases, atopic dermatitis (AD), allergic contact dermatitis (ACD), and psoriasis, provides a unique opportunity to directly investigate epicutaneous, molecular biomarkers in humans. We hypothesize that molecular biomarkers for chronic itch are defined as a set of transcriptional units (both messenger and micro RNAs) and resident bacteria that are upregulated and shared in skin lesions that chronically itch. We are currently using metagenomics to identify the biomarkers.