Paul A. Khavari, MD, PhD

Research/Lab website:   Khavari Lab

Our experimental focus is on the mammalian setting, including mouse genetics, human genetics and new human tissue platforms. The latter encompass human skin regenerated on immune deficient mice as well as organotypic constructs with epithelial and stromal cells embedded within architecturally faithful mesenchyma in vitro. These new models, which we term Multi-Functional Human Tissue Genetics, allow up to 10 alleles or more to be altered simultaneously, permitting genetic experiments with an unprecedented degree of rapidity and complexity.

Stem cell biology and differentiation

In stratified epithelia proliferative basal cells adherent to the underlying basement membrane undergo cell cycle arrest then outward migration and terminal differentiation. This process is mediated by 2 mutually exclusive programs of gene expression: 1) an undifferentiated program supporting proliferation by stem cells within the basal layer and 2) a differentiation program instructing growth arrest and differentiation-associated programmed cell death in suprabasal layers. The control of this transition from epithelial stem cell to differentiated corneocyte, which is abnormal in epidermal cancers, is not well understood. We are currently pursuing studies of the dominant signaling and gene regulatory networks that control this process, including the Ras/MAPK cascade, which is required for stem cell-mediated self-renewal and the p53 transcription factor family member, p63, which is required for epidermal differentiation.

Epigenetic regulation by histone modifying proteins and noncoding RNA

In addition to classical gene regulatory networks noted above, we have recently identified a central role for additional biologic mechanisms, namely gene regulation by chromatin regulators and by noncoding RNAs. Epigenetic control of gene expression lasts through multiple cell divisions without alterations in primary DNA sequence and can occur via mechanisms that include histone modification and DNA methylation. Noncoding RNA sequences can regulate gene expression via interactions with epigenetic and other control mechanisms. The function of histone modifying epigenetic regulators and noncoding RNA as central mediators of epithelial stem cell renewal and differentiation represent major emerging areas of study in the lab.

Cancer

Skin malignancies, including epidermal squamous cell carcinoma (SCC), alone account for nearly as many cancers as all other tissues combined. Progress in understanding epithelial carcinogenesis has been hindered in the past by a lack of models that faithfully recapitulate the 3-dimensional architecture of tumor-stroma co-evolution. To address this and to also study the oncogenic potential of unregulated function of dominant regulators of epithelial homeostasis noted above, we developed Multi-Functional Human Tissue Genetics noted above which, when combined with skin tissue regeneration on immune deficient mice, has permitted the molecular reconstruction of events sufficient to trigger human cancer. These models are being used to systematically elucidate proteins required for cutaneous carcinogenesis and to test their potential role as therapeutic targets.

Molecular Therapeutics

Epithelial tissues in general and skin in particular offer an attractive site for development of new approaches in molecular therapeutics. A family of human genetic skin diseases is characterized by defective epithelial gene expression. Among the most severe of these are subtypes of epidermolysis bullosa (EB) and lamellar ichthyosis (LI). We have developed approaches for high efficiency gene transfer to EB and LI patient skin tissue that are corrective at biochemical, histologic, clinical and functional levels. In addition to EB subtypes and LI, similar corrective efforts have also been undertaken with a number of other genetic skin disorders.