Description of Research Program
Both basic and translational research related to skin biology, skin inflammation and skin cancer (melanoma and non-melanoma) are currently undertaken in the Indra Lab.
Several projects centered around basic research includes :
a) Mechanism(s) of development of skin epidermis in space and time from stem/progenitor cells. Skin develops in space and time from stem cells. The mechanisms of transcriptional networks and signaling that are operational during development are currently investigated using cellular, molecular and genetic approaches. We discovered that transcription factor Ctip2 is expressed in the hair bulge (hair follicle stem cell reservoir), in all of the epidermal basal cells, and plays crucial role(s) in the intrinsic control of (i) epidermal proliferation, (ii) dynamic switch from proliferation to differentiation, and (iii) terminal differentiation. In vitro, ex vivo and in vivo studies are underway to reveal the downstream signaling pathways and to integrate the multiple transcriptional networks that mediate and regulate the steps towards formation of a mature skin (In collaboration with G. Ganguli-Indra and M. Leid, OSU).
b) The mechanisms of establishment of protective skin barrier and control of skin lipid metabolism. Skin, which acts as a protective shield from outside, has several vital functions. The mechanisms underlying establishment of the epidermal permeability barrier (EPB) is poorly understood. Genetic and somatic mutations of genes implicated in barrier formation can lead to impaired barrier functions, increases susceptibility to skin inflammatory diseases such as eczema, atopic-asthma and in more severe form cause neonatal deaths in humans. Current research in the lab is centered to improve our understanding of the genetic, epigenetic and somatic alterations that leads to impaired barrier formation using novel animal models developed in our group. Lipids play an integral part in the impermeability of the epidermal barrier and alterations in expression of the genes implicated in skin lipid metabolisms can lead to a leaky barrier. Mass spectroscopy based lipidomics studies to determine changes in lipid composition followed by reverse genetics approaches to elucidate the molecular mechanisms, are currently underway in our pre-clinical animal models. Mouse genetics, cell and molecular biology approaches are undertaken to reveal the molecular network controlling barrier formation [In collaboration with F. Stevens and G. Ganguli-Indra (OSU), Eric Simpson and John Hanifin (OHSU)].
c) Cell–> cell signaling for maintenance of skin homeostasis and UV irradiation induced photocarcinogenesis. Solar UV irradiation is an important etiological risk factor for melanoma and non-melanoma skin cancer. Research is aimed at understanding how skin cells such as keratinocytes and melanocytes signal and communicate between each other in normal and in disease conditions. Nuclear hormone Receptors (NRs) particularly Retinoid-X-Receptors (RXR a, b and g) plays important roles in skin during development, and in adult skin homeostasis. To circumvent the problems of early lethality associated with conventional gene targeting and the complex pleiotrophic gene effects, we developed a spatio temporally controlled somatic mutagenesis technique based on the bcteriophage P1-Cre/ lox strategy. Using that genetic tool we have selectively ablated NRs and in particular RXRa in keratinocytes, melanocytes and in fibroblast to address its role in (i) skin ontogenesis and in adult skin homeostasis, (ii) stress responses like temperature shock, solar UV induced skin tanning and photo ageing, (iii) various skin diseases, and in (iv) melanoma and non-melanoma skin cancer. Gene expression analysis and microRNA profiling are currently being performed for identification of novel UV signature sequences as a predictive tool for cancer progression in novel pre-clinical animal models [In collaboration with G. Ganguli-Indra (OSU), Z. Abdel-Malek (Univ. Cincinnati), P Chambon and D. Metzger (IGBMC, France), Lionel Larue (Institut Curie, France)].
d) Nuclear receptor signaling in tumor microenvironment during melanoma progression. In skin, RXRs and in particular RXRa plays a key role in transducing cellular signals through hetero-dimerisation with other NR members like Retinoic Acid Receptors (RARs), Vitamin-D-Receptor (VDR), Peroxisome-Proliferator Activated Receptors (PPARs) and Liver-X-Receptors (LXRs) in presence of their cognate ligands. We recently discovered that keratinocytic RXRa in combination with activated CDK4 developed invasive melanomas in a novel mouse model. Through selective ablation of NRs in keratinocytes or in melanocytes, we are determining their role in melanoma progression and malignant conversion within the tumor microenvironment. The co-operativity between NR signaling and Ras-Raf or Pten-Akt signaling pathways are also being investigated [In collaboration with G. Ganguli-Indra (OSU), P Chambon and D. Metzger (IGBMC, France), L. Larue (Pasteur Institute, France), F. Beermann (ISREC, Switzerland)].
Current studies are directed towards use of our pre-clinical animal model(s) for screening of novel compounds such as small molecule modulators, natural compounds to prevent and treat melanoma [T. Mahmud (OSU), Z. Abdel-Malek (Univ. Cincinnati)].
Translation research in the Indra group is centered around:
(a) Developing novel cancer bio-markers for early diagnosis and predicting disease progression in humans [In collaboration with G. Ganguli-Indra, M. Leid (OSU) and M. Kulesz-Martin (OHSU)].
(b) Developing nano-biosensors for early and accurate detection of markers in human cancer [In collaboration with G. Ganguli-Indra, E. Minot and V. Remcho (OSU)].
(c) Identification of signature changes in lipid profiles from eczema, atopic dermatitis (AD) and allergic contact dermatitis (ACD) patients using lipidomics platform [In collaboration with Fred Stevens (OSU), E. Simpson and J. Hanifin (OHSU)]
(d) Characterization of novel signature changes/mutations during spontaneous and UV induced melanoma progression in humans for better prognosis and diagnosis in human patients.
(e) Identification of novel signatures (e.g. microRNA profiles) in skin immune cells and epidermal keratinocytes in psoriasis patients [In collaboration with A. Blauvelt (OHSU)].