Key Documents
Paul A. Khavari, MD, PhD
- Professor, Dermatology
- Member, Bio-X
- Member, Cancer Center
Contact Information
- Clinical Offices
Dermatology Clinic 900 Blake Wilbur Dr W0001 MC 5334 Stanford, CA 94305 Telephone Work (650) 723-6316 Fax (650) 723-7796
- Academic Offices
Personal InformationAdministrative Contact Pam Bernstein Program Director Email pbb@stanford.edu Tel Work 650/498-6295
Postdoctoral Advisees
Graduate & Fellowship Program Affiliations
Web Site Links
Industry Relationships
Stanford is committed to ethical and transparent interactions with our industry partners. It is our policy to disclose payments of $5,000 or more, equity valued at $5,000 or more in a publicly traded company, or any equity in a privately held company, to physicians and scientists employed by Stanford University from companies or other commercial entities with which they interact as part of their professional activities.
- Consulting: Johnson and johnson
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 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.
Clinical Trials
Publications
- Cancer Cell. 2009; (6): 477-88
- Genes Dev. 2008; (14): 1865-70
- Dev Cell. 2007; (4): 615-29
- Science. 2005; (5716): 1773-6
- Nat Genet. 2005; (7): 745-9
- J Cell Biol. 2005; (4): 561-6
- Semin Cancer Biol. 2004; (1): 63-9
- Genes Dev. 2004; (1): 17-22
- Cancer Res. 2004; (17): 6035-40
- Mol Ther. 2004; (5): 721-8
- Nat Biotechnol. 2004; (4): 393-4
- Cell Cycle. 2004; (5): 621-4
- Mol Ther. 2004; (1): 93-100
- Cell Cycle. 2003 Mar-Apr; (2): 79-80
- Hum Gene Ther. 2003; (9): 923-8
- Gene Ther. 2003; (13): 1099-104
- J Clin Invest. 2003; (2): 251-5
- Hum Gene Ther. 2003; (13): 1225-33
- Cancer Res. 2003; (2): 319-23
- Nature. 2003; (6923): 639-43
- Oncogene. 2003; (13): 1955-64
- J Cell Biol. 2002; (1): 103-12
- J Intern Med. 2002; (1): 1-10
- Nature Medicine. 2002; 1166-1170
- Oncogene. 2002; (10): 1527-38
- Nat Med. 2002; (10): 1105-14
- Nat Med. 2002; (10): 1166-70
- Biotechniques. 2002; (1): 190-2, 194
- Hum Gene Ther. 2001; (12): 1551-8
- Proc Natl Acad Sci U S A. 2001; (9): 5193-8
- Hum Gene Ther. 2001; (11): 1443-8
- Cancer Res. 2000; (15): 4085-92
- Nat Med. 2000; (11): 1253-7
- Hum Gene Ther. 2000; (16): 2277-82
- J Clin Invest. 2000; (3): 253-60
- Hum Gene Ther. 2000; (16): 2245
- Trans Am Clin Climatol Assoc. 1999; 86-92
- Nat Biotechnol. 1999; (9): 870-2
- Gene Ther. 1999; (1): 42-7
- J Cell Biol. 1999; (1): 71-6
- Arch Dermatol. 1998; (3): 382-3
- J Invest Dermatol. 1998; (4): 462-7
- J Invest Dermatol. 1998; (1): 8-12
- J Am Acad Dermatol. 1998; (2 Pt 2): 325-9
- Arch Dermatol. 1998; (6): 745, 747-8
- Biotechniques. 1998; (2): 274-80
- Proc Natl Acad Sci U S A. 1998; (5): 2307-12
- Nat Med. 1997; (7): 788-92
- Hum Gene Ther. 1997; (14): 1659-65
- Nat Biotechnol. 1997; (13): 1388-91
- J Clin Invest. 1997; (11): 2610-5
- Hum Gene Ther. 1997; (8): 895-901
- Dermatol Clin. 1997; (1): 27-35
- Mol Med Today. 1997; (12): 533-8
- Nat Med. 1997; (6): 612-3
- Hum Mol Genet. 1997; (6): 927-33
- J Invest Dermatol. 1997; (2): 215-9
- EMBO J. 1996; (19): 5370-82
- J Biol Chem. 1996; (49): 31666-9
- Nat Med. 1996; (11): 1263-7
- Hum Gene Ther. 1996; (18): 2247-53
- J Am Acad Dermatol. 1996; (6): 907-10
- Dev Biol. 1994; (1): 229-42
- Cell. 1994; (1): 119-30
- Nature. 1994; (6489): 477-81
- Nature. 1993; (6451): 170-4
- Science. 1991; (5039): 1762-7
- Arch Dermatol. 1991; (4): 543-6
- Yale J Biol Med. 1987 Sep-Oct; (5): 409-19
- J Immunol. 1987; (2): 380-4
- Appl Microbiol. 1967; (3): 564-5