Khavari Lab In The Department of Dermatology

Stem Cell Biology, Cancer and Molecular Therapeutics

The Khavari Lab uses epithelial tissue as a model system to study stem cell biology, cancer and new molecular therapeutics. Epithelia cover external and internal body surfaces and undergo constant self-renewal while responding to diverse environmental stimuli. Epithelial homeostasis precisely balances stem cell-sustained proliferation and differentiation-associated cell death, a balance which is lost in many human diseases, including cancer.

Epithelial neoplasms, including those affecting the skin, represent approximately 90% of all human malignancies. Our experimental focus is on the mammalian setting for enhanced medical relevance. We use classical mouse genetics, human genetics and novel 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 mesenchymal tissue in vitro. These new models allow up to 10 alleles or more to be altered simultaneously, permitting genetic experiments with an unprecedented degree of rapidity and complexity exceeding that previously possible in classic genetic functionator organisms, such as yeast, worms and flies. These new genetic models, which we group under the new term Multi-Functional Human Tissue Genetics, have facilitated the first conversions of normal human tissue into invasive cancer via alterations in defined genetic networks.

For functional studies, we use an array of genetic interventions, including targeted gene disruption, RNA interference (RNAi) and conditionally active alleles, as well as pharmacologic and biochemical technologies. Bioinformatics-intensive systems biology methods are used alongside classical morphogenetic assessments to define critical regulators of homeostasis and neoplasia as a basis for targeted molecular therapeutics.

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