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Background
Background
Type 2 diabetes (T2D) is a complex disease that affects around 34.1 million adults in the U.S.. Several risk factors are traditionally linked to the development of T2D, including body weight, level of physical activity, and genetic predisposition. Over the past several years, there has been growing evidence demonstrating an association between psoriasis, a chronic inflammatory skin disease, and increased risk for type 2 diabetes (T2D). In particular, patients with psoriasis lesions that cover greater than 10% of their body are 64% more likely to develop diabetes than those without psoriasis, independent of traditional risk factors. This link is important since the combination of psoriasis and T2D worsens glycemic control to a greater degree, leading to increased secondary complications than either disease alone. There are currently no proven treatment strategies to prevent T2D development in psoriasis patients. Thus, our lab focuses on identifying the molecular mechanisms linking chronic skin inflammatory diseases, such as psoriasis and metabolic dysfunction to develop novel therapeutic intervention using murine models and human samples.
Project Areas
Epigenetic regulation of structural/ immune cell inflammation profile in psoriasis
Epigenetic regulation of gene expression plays a key role in influencing structural and immune cell phenotype during chronic skin inflammation. In particular, chromatin modifications influence structural and immune cell phenotype by controlling downstream protein expression patterns. Histone methylation and demethylation play a role in regulating structural and immune cell gene expression. Methylation of a histone activates or represses transcription depending on the number of methyl groups added and their location on the histone tail. Methylation and demethylation of histone tails is carried out by chromatin modifying enzymes (CMEs). In this regard, CMEs in structural and immune cells are important for controlling gene expression and promoting pathology in other chronic diseases; however, little is known about the epigenetic regulation of keratinocytes/immune cells by CMEs in psoriasis. Interestingly, our current single-cell and bulk RNAseq data indicate several CMEs dysregulated in structural and immune cells in psoriasis lesional skin. Projects in this area seek to understand the role of these CMEs in psoriasis pathogenesis through functional in vitro and in vivo studies in order to develop novel cell-specific therapeutic intervention.
Understand the molecular mechanism(s) by which psoriasis skin inflammation drives metabolic dysfunction
Recent studies show that psoriasis skin inflammation drives adipose tissue inflammation, indicated by increased inflammatory immune cells, and impaired glucose metabolism. In this regard, it is likely that cytokines/mediators generated in the skin are released into the bloodstream and travel to more distant sites where they influence inflammation. Keratinocytes, the main structural cell type in the epidermis of the skin, are primed to respond to environmental stimuli and serve as the first link in psoriasis pathogenesis. Following initial insult, keratinocytes secrete multiple cytokines (i.e., type I interferons (T1IFNs), IL-36, IL-6) that can regulate immune cell phenotype in local and distant tissues driving psoriasis inflammation. While current research has focused on how keratinocyte-derived cytokines can contribute to local inflammation, little progress has been made in understanding which keratinocyte immune interactions are important for driving systemic inflammation and metabolic dysfunction, leading to increased risk for type 2 diabetes. Projects in this area seek to understand the molecular mechanism(s) by which keratinocyte inflammatory immune interactions induce psoriasis-mediated metabolic dysfunction using human samples and murine models.
Cell-specific targeting of key inflammatory pathways
Current biologics for psoriasis target broad pathways in a global non-cell specific manner. There are currently no proven cell-specific treatment strategies to improve psoriasis pathogenesis or limit the progression of systemic disease activity resulting in comorbidity development. Projects in this area focus on targeting novel inflammatory pathways shown to be dysregulated within people psoriasis and type 2 diabetes in a cell-specific manner.
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