Paul A. Khavari, MD, PhD

Research/Lab website:   Khavari Lab

Regulation of epithelial growth and carcinogenesis
Epithelia display two broad and mutually exclusive programs of gene expression: 1) an undifferentiated program that mediates proliferation and adhesion to the underlying basement membrane and 2) a growth arrest program that mediates terminal differentiation. We have demonstrated that maintenance of the undifferentiated state is dependent on Ras signaling proteins and that the transition to growth arrest involves spatially regulated activation of NF-kB/Rel gene regulators. Without Ras function, epithelium loses proliferative renewal and undergoes terminal differentiation. Without NF-kB, epidermal cells fail to exit the proliferative compartment, leading to epidermal hyperplasia. To study interactions between dominant regulators such as Ras and NF-kB, we have developed multiplex serial gene transfer (MSGT) in which alterations in 8 or more signaling networks can be made simultaneously in normal tissue. Combining MSGT with the capacity to regenerate human skin tissue on immune deficient mice has permitted the molecular reconstruction of events sufficient to trigger human cancer and facilitated development of human tissue models of basal cell carcinoma, squamous cell carcinoma and malignant melanoma. These models are being used to systematically elucidate proteins required for carcinogenesis and to test their potential as therapeutic targets. Complementing these studies, we have pursued a genome-wide screening approach using array-based transcript profiling to characterize genes expressed in epidermal cancers and at specific steps in the transition from epithelial stem cell to growth arrested terminally differentiating cell. From these efforts, we have identified a host of previously uncharacterized genes altered in carcinogenesis that also appear part of precisely controlled genetic programs that control epithelial growth and differentiation. In combination, these studies are providing a broad perspective on the genetic controls of epithelial cell proliferation and are linking this information to human epithelial diseases.

Molecular therapeutics for epithelial tissue
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 [LAMB3, BPAG2, COL7A1 genes] and LI [TGM1 gene], similar corrective efforts have also been undertaken with a number of other genetic skin disorders, including X-linked ichthyosis [STS] and xeroderma pigmentosum [XPC]. These studies have been extended to refine new vectors capable of sustainable therapeutic gene delivery to epidermis as a basis for initiating clinical trials in humans. In addition to these efforts at molecular correction of genetic skin disorders, new approaches for genetic vaccination and systemic gene delivery via the skin have also been established. Moreover, an array of nonviral and viral vectors has been used to achieve regulated delivery of therapeutic polypeptides to the bloodstream via cutaneous gene transfer. As a complement to gene-based therapeutics, we are studying new ways to introduce proteins and small molecule pharmacotherapeutics through the epidermal permeability barrier using conserved transporter domains. Finally, the potential of antibodies to alter cellular receptors and matrix interactions important in cancer are being analyzed using the capacity to develop genetically defined human cancers noted above. All of these efforts are aimed to advance progress in the application of molecular therapeutics to epithelial tissues.