The development of the skin from intrauterine to extrauterine life is an orchestrated interplay of epidermal proliferation, terminal differentiation, and barrier formation. Failure to construct an epidermal permeability barrier (EPB), which is a life-threatening problem in the majority of premature infants, results in increased transepidermal water loss with concomitant dehydration and electrolyte imbalance, as well as fragile skin. Barrier defects are also believed to contribute to several hereditary and acquired inflammatory skin disorders, such as psoriasis and atopic dermatitis (AD). Thus, understanding the pathways that are controlled by different regulatory proteins (e.g., transcription factors) in skin is the key for the development of effective treatments for the various skin diseases described above, as well as epithelial cell skin cancers, including head and neck squamous cell carcinoma (HNSCC). Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2, also known as Bcl11b) is a transcriptional regulatory protein that is highly expressed in skin during mouse development, as well as in proliferating cells of the adult mouse. We have recently discovered that germline deletion of CTIP2 in mice results in a severe skin phenotype characterized by compromised EPB formation, and dramatically reduced epidermal thickness. We have also observed striking upregulation of CTIP2 in several human HNSCC biopsies, in which the level of CTIP2 expression was inversely correlated with the degree of differentiation of the tumor, i.e., poorly differentiated tumors were found to express very high levels of CTIP2 while highly differentiated tumors expressed very little CTIP2. However, the cellular and molecular mechanism underlying the activity of CTIP2 in skin during epidermal homeostasis and barrier formation is not known. Similarly, we do not understand the role of CTIP2 in proliferative events during skin development or in proliferative diseases of adults, such as HNSCC. Lack of this knowledge is a critical problem in our understanding of the biological roles of the CTIP2 in human health and disease. The long-term goal of this laboratory is to elucidate the molecular and cellular mechanisms that underlie the actions of CTIP2 in fetal, neonatal, and adult skin, and in proliferative diseases of the skin, towards the goal of extrapolating to the human situation. Based on the above observations and from the preliminary data, we propose the following three Specific Aims: (1) to elucidate the cellular and molecular mechanism(s) underlying the role of CTIP2 in EPB formation, (2) to elucidate the cellular and molecular mechanism(s) of CTIP2 action in epidermal proliferation/differentiation, and (3) to determine the role of CTIP2 in pathogenesis of head and neck squamous cell carcinoma. The proposed research is innovative because it will, for the first time, reveal the cellular and molecular mechanisms by which CTIP2 regulates skin organogenesis, EPB formation, and tissue homeostasis. We believe that this research will have significant, positive effects on human health because these outcomes will provide an enhanced understanding of regulatory influences on epidermal keratinocyte proliferation, differentiation and EPB formation, which may lead to development of more efficacious treatment paradigms for the human disorders, such as atopic dermatitis, and possibly HNSCC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056008-05
Application #
8264588
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2008-08-26
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$293,652
Indirect Cost
$84,564
Name
Oregon State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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Guha, Gunjan; Lu, Wanli; Li, Shan et al. (2015) Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) Cells. PLoS One 10:e0125322
Bhattacharya, Shreya; Wheeler, Heather; Leid, Mark et al. (2015) Transcription Factor CTIP2 Maintains Hair Follicle Stem Cell Pool and Contributes to Altered Expression of LHX2 and NFATC1. J Invest Dermatol 135:2593-602
Ummadi, J Ganesh; Joshi, Vrushali S; Gupta, Priya R et al. (2015) Single-Cell Migration as Studied by Scanning Electrochemical Microscopy. Anal Methods 7:8826-8831
Ganguli-Indra, Gitali (2014) Protocol for cutaneous wound healing assay in a murine model. Methods Mol Biol 1210:151-9
Wang, Zhixing; Kirkwood, Jay S; Taylor, Alan W et al. (2013) Transcription factor Ctip2 controls epidermal lipid metabolism and regulates expression of genes involved in sphingolipid biosynthesis during skin development. J Invest Dermatol 133:668-76
Indra, Arup K (2013) Epidermal TSLP: a trigger factor for pathogenesis of atopic dermatitis. Expert Rev Proteomics 10:309-11
Wang, Zhixing; Zhang, Ling-Juan; Guha, Gunjan et al. (2012) Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice. PLoS One 7:e51262
Zhang, Ling-juan; Bhattacharya, Shreya; Leid, Mark et al. (2012) Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling. J Cell Sci 125:5733-44
Liang, Xiaobo; Bhattacharya, Shreya; Bajaj, Gaurav et al. (2012) Delayed cutaneous wound healing and aberrant expression of hair follicle stem cell markers in mice selectively lacking Ctip2 in epidermis. PLoS One 7:e29999

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