Fibroblasts are the principal cells that reside in the dermis of the skin and stroma of all vertebrate organs. Although fibroblasts were thought by many to be homogenous, we have discovered that human fibroblasts from different anatomic sites of the skin and internal organs constitute many distinct, differentiated cell types that carry out unique genetic programs to specify the site-specific design and functions of epithelial organs. The broad goal of this project is to understand the physiologic specialization and developmental regulation of fibroblasts by following the expression level of a large number of genes in cultured fibroblasts. Firstly, using high density cDNA microarrays and computational bioinformatics, we will create a comprehensive molecular map of fibroblast gene expression patterns from diverse site in the human body. This large compendium of fibroblast gene expression patterns will reveal how many different types of fibroblasts exist, how they are related to one another, and where they are located in the human body. The gene expression programs that characterize specific fibroblasts will define the physiologic specialization of different fibroblast cell types and will help to explain the inductive potentials of fibroblasts in development, their functions during tissue repair, and the anatomic specificity of diseases affecting skin and connective tissues. Secondly, the site-specific gene expression profiles of fibroblasts will be used as tools to understand how different types fibroblasts develop. By assessing the gene expression patterns of fibroblasts from different sites cultured together and of fibroblasts cultured in isolation from one another, we will address whether fibroblasts instruct each other to adopt site-specific fates, or whether the differentiation program is controlled autonomously within each cell. Thirdly, adult fibroblasts have the unique property of maintaining positional memory, preserved in the form of Hox gene expression patterns established during embryogenesis. Hox genes encode a family of transcription factors that activate other genes to specify positional identities in development. We will test whether Hox genes are master regulators of fibroblast differentiation by assessing the gene expression patterns of fibroblasts with ectopic or inactivated Hox functions. From the proposed experiments, we hope to learn a great deal about the gene expression programs in fibroblast differentiation. This knowledge will provide many basic insights into wound healing, organ development, anatomic specificity of genetic and acquired diseases affecting the skin and connective tissues; and shed light on how positional identity is acquired and maintained in the human body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR050007-03
Application #
7100221
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Lapham, Cheryl K
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$117,747
Indirect Cost
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rinn, John L; Wang, Jordon K; Liu, Helen et al. (2008) A systems biology approach to anatomic diversity of skin. J Invest Dermatol 128:776-82
Rinn, John L; Wang, Jordon K; Allen, Nancy et al. (2008) A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev 22:303-7
Adler, Adam S; Sinha, Saurabh; Kawahara, Tiara L A et al. (2007) Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev 21:3244-57
Chang, Howard Y (2007) Patterning skin pigmentation via dickkopf. J Invest Dermatol 127:994-5
Rinn, John L; Kertesz, Michael; Wang, Jordon K et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311-23
Nuyten, Dimitry S A; Kreike, Bas; Hart, Augustinus A M et al. (2006) Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 8:R62
Adler, Adam S; Lin, Meihong; Horlings, Hugo et al. (2006) Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38:421-30
Rinn, John L; Bondre, Chanda; Gladstone, Hayes B et al. (2006) Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet 2:e119
Adler, Adam S; Chang, Howard Y (2006) From description to causality: mechanisms of gene expression signatures in cancer. Cell Cycle 5:1148-51
Wong, David J; Chang, Howard Y (2005) Learning more from microarrays: insights from modules and networks. J Invest Dermatol 125:175-82

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