Cell signaling, skin development, stem cell biology, inflammatory skin disease, melanoma, tumor microenvironment, Mouse genetics, and transcriptional regulation.
Our laboratory is investigating into the mechanisms of skin development in space and time from stem cells using mouse genetics, biochemical, cellular and molecular approaches. We have identified key factors that are essential in establishment and maintenance of a protective epidermal barrier, lack of which can lead to neonatal death or in a milder form can trigger onset of inflammatory skin diseases such as Atopic dermatitis (AD). The mechanism(s) of skin barrier formation and contribution of skin keratinocytes in triggering such immune responses in presence of a leaky barrier are being investigated.
In collaboration with laboratory of Mark Leid (Pharmacology), we have discovered that transcriptional regulatory protein Ctip2/Bcl11b regulates key processes during skin formation. The mechanisms of activation of Ctip2/Bcl11b with response to external cues, it’s dynamic role in integrating with multiple other signaling cascades, thus allowing formation of an intact and healthy skin are some areas of active research. A lipidomics approach for profiling skin lipids and predicting disease progression in human AD patients are currently underway in collaboration with faculties at OHSU and OSU.
The mechanisms by which many of these developmental processes are dysregulated in cancer is another focus area of research. We are studying the cell-cell signaling that are functional within a tumor-microenvironment and contributing to cancer metastasis. We have discovered that nuclear receptor (NR) signaling between skin keratinocytes & pigment producing melanocytes mediated by Retinoid-X-Receptor α (RXRα) heterodimerization with other NRS, can contribute to formation of malignant melanomas. The crosstalk between NR signaling with other signaling pathways and their role in mediating melanoma metastasis and de-differentiation are being investigated. Solar UV irradiation induced skin tanning (pigmentation) and photoaging are some other areas of active research.
We have developed and characterized several pre-clinical models of human diseases such as those exhibiting skin barrier defects (icthyosis), atopic dermatitis, skin pigmentation disorder, and for invasive melanomas. In collaboration with medicinal chemists (Taifo Mahmud, Fred Stevens), we are utilizing these animal models to screen for natural compounds as new drug leads for effective therapeutic intervention.
Collaborative Translational Research Projects
• Developing novel cancer bio-markers for early diagnosis and predicting disease progression in human head and neck cancers.
• Developing nano-biosensors for early and accurate detection of markers in human cancers
• Identification of signature changes in lipid profiles from eczema, atopic dermatitis (AD) and allergic contact dermatitis (ACD) patients using lipidomics.
• Characterization of novel signature alterations/mutations during spontaneous and UV induced melanoma progression in humans for improved prognosis and diagnosis.
• Identification of novel signatures (e.g. microRNA profiles) in different skin cells of psoriasis patients.
Indra G., Wasylyk C., Liang X., Millon R., Leid M., Wasylyk B., Abecassis J., Indra A.K. (2009) CTIP2 expression in human head and neck squamous cell carcinoma is linked to poorly differentiated tumor status. PLoS ONE.4(4):e5367. Apr 28:1-12.
Indra, G. #, Hyter, S., Liang, X. Hanifin, J and Indra, A.K. (2009) Expression of Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2) in human inflammatory skin diseases. Experimental Dermatol. Mar 29: 1-3.
Golonzhka, O., Liang, X., Messaddeq, N., Bornert, J.M., Campbell, A., Metzger, D., Chambon,P., Indra, G., Leid, M#. and Indra, A.K. # (2008). Dual role of COUP-TF-interacting protein 2 (CTIP2) in regulating epidermal homeostasis and skin barrier formation during mouse fetal development. JID (NPG). 2009 Jun;129(6):1459-70. Epub 2008 Dec 18.
Ocadiz-Delgado R., Castaneda-Saucedo E, Indra A.K., Hernández-Pando R and Gariglio P. (2008). Impaired cervical homeostasis upon selective ablation of RXRa in epithelial cells. Genesis. Jan;46(1):19-28.
Fadloun A., Kobi D., Pointud J.C., Indra A.K., Teletin M., Bole-Feysot C., Testoni B., Mantovani R., Metzger D., Mengus G. and Davidson I. (2007). The TFIID subunit TAF4 regulates keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis. J Cell Sci. 2007 Aug 15;120 (Pt 16):2752.
Indra A.K.*, Castaneda, E., Antal, M.C., Jiang, M., Messaddeq, N., Meng, X., Loehr, C., Gariglio, P., Kato, S., Wahli, W., Desvergne, B., Metzger, D. and Chambon, P* (2007). Malignant transformation of DMBA/TPA-induced papillomas and melanocytic growths in th skin of mice selectively lacking Retinoid X Receptor alpha (RXRa) in epidermal keratinocytes. J Invest Dermatol. [NPG] May;127(5):1250-60.
Indra AK, Dupe V, Bornert JM, Messaddeq N, Yaniv M, Mark M, Chambon P, Metzger D. Temporally controlled targeted somatic mutagenesis in embryonic surface ectoderm and fetal epidermal keratinocytes unveils two distinct developmental functions of BRG1 in limb morphogenesis and skin barrier formation. Development. 2005;132(20):4533-44.
Indra AK, Mohan WS 2nd, Frontini M, Scheer E, Messaddeq N, Metzger D, Tora L. TAF10 is required for the establishment of skin barrier function in foetal, but not in adult mouse epidermis. Developmental Biology. 2005;285(1):28-37.
Metzger D, Li M, Indra AK, Ghyselinck G, Chambon P. Conditional knockouts: Cre-lox systems. In: Celis J, ed. CELL BIOLOGY: A Laboratory Handbook, 3rd Ed. San Diego: Elsevier Inc.; 2004
Metzger D, Indra AK, Li M, Chapellier B, Ghyselinck G, Chambon P. Targeted conditional somatic mutagenesis in the mouse: temporally controlled knock-out of the retinoid receptors in epidermal keratinocytes. Methods in Enzymology. Vol 364, 2003.
Indra AK, Li M, Brocard J, Warot X, Bornert JM, Gerard C, Messaddeq N, Chambon P, Metzger D. Targeted somatic mutagenesis in mouse epidermis. Hormone Research. 2000;54(5-6):296-300.
Indra AK, Li M, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature. 2000;407(6804):633-6.
Indra AK, Warot X, Brocard J, Bornert JM, Xiao JH, Chambon P, Metzger D. Temporally controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Research. 1999;27(22):4324-7.