Paul A. Khavari, MD, PhD

Postdoctoral Advisees

Xiaomin Bao, Ross Flockhart, Markus Kretz, Carolyn Lee, Vanessa Lopez-Pajares, Todd Ridky, George Sen, Brian Zarnegar

Graduate & Fellowship Program Affiliations

• Cancer Biology
• Dermatology

Web Site Links

• Khavari Lab

Industry Relationships

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Research Interests

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...

Clinical Trials

• Characteristics of Adult Patients with Recessive Dystrophic Epidermolysis Bullosa Recruiting
• Characteristics of Patients with Dystrophic Epidermolysis Bullosa Recruiting

Publications

• Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression. Reuter JA, Ortiz-Urda S, Kretz M, Garcia J, Scholl FA, Pasmooij AM, Cassarino D, Chang HY, Khavari PA. Cancer Cell. 2009; 15 (6): 477-88
• Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA. Genes Dev. 2008; 22 (14): 1865-70
• Mek1/2 MAPK kinases are essential for Mammalian development, homeostasis, and Raf-induced hyperplasia. Scholl FA, Dumesic PA, Barragan DI, Harada K, Bissonauth V, Charron J, Khavari PA. Dev Cell. 2007; 12 (4): 615-29
• Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Ortiz-Urda S, Garcia J, Green CL, Chen L, Lin Q, Veitch DP, Sakai LY, Lee H, Marinkovich MP, Khavari PA. Science. 2005; 307 (5716): 1773-6
• Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Chudnovsky Y, Adams AE, Robbins PB, Lin Q, Khavari PA. Nat Genet. 2005; 37 (7): 745-9