Cellular and Molecular Physiology / Tamás Bíró

Personal data: 

 

Tamás Bíró
M.D., Ph.D., Associate Professor
E-mail: birophys[at]med.unideb.hu

 

http://phys.dote.hu

 

 

Research: 

Background
The human skin and its appendages (hair follicles, sebaceous and sweat glands) function as “active” neuro-immuno-endocrine organs. Indeed, the skin contains well-defined neuronal networks; a wide-array a constantly remodeling non-neuronal cells; and an orchestrated immunological machinery producing numerous mediators. The proper execution of cutaneous neuro-immuno-endocrine functions and the establishment of the physiological skin homeostasis are strongly dependent on “life-long” regeneration and rejuvenation of cutaneous non-neuronal cells and “mini-organs”. These are defined by the organized, delicate balance of cellular/organ proliferation and growth, survival and death, and regulated by multitude of soluble mediators released from the skin cells.

Recently, two endogenous systems, i.e. certain TRP ion channels as well as the endocannabinoid system, have been identified in the human skin and were implicated in crucial regulatory processes affecting both skin health and disease.

Previous Results
Members of the transient receptor potential (TRP) ion channel superfamily function as “cellular sensors” of e.g. temperature challenges, osmotic changes, taste, etc. However, we have previously

shown that transient receptor potential vanilloid-1 (TRPV1, the “capsaicin” receptor),

 

             Figure 1. Schematic structure of TRPV1

which was originally described on sensory afferents as a central integrator molecule of pain sensation, is functionally expressed on numerous non-neuronal cell populations on the human skin. Indeed, activation of TRPV1 was found to (i) inhibit growth and proliferation and induce apoptosis in organ-cultured human hair follicles and in cultured human epidermal keratinocytes; (ii) suppress basal and inflammation-induced lipid production on human sebaceous gland-derived sebocytes; and (iii) markedly alter gene expression profiles as well as productions of a wide-array of cytokines and hormones of

Figure 2. TRPV1 activation inhibits human hair growth and induces intrafollicular apoptosis in vitro
a) Activation of TRPV1 by capsaicin (Caps) in human hair follicle organ-culture inhibits hair shaft elongation. *p<0.05.

b) Treatment of hair follicles by Capsaicin (10 μM) for 5 days results in stimulation of apoptosis (TUNEL labeling, green) and suppression of proliferation (Ki67 labeling, red).

 

Furthermore, our preliminary findings also suggest that other TRP channels (e.g. TRPV3, TRPA1) are also expressed in the human epidermis and hair follicles and that the activation of these channels may modulate skin cell growth.

Numerous TRP channels can be activated by various endogenous lipid mediators such as e.g. certain endocannabinoids. Of importance, the closely related endocannabinoid system (ECS) was also identified in the human skin. Indeed, we have successfully identified the production of prototypic endocannabinoids, i.e. anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol, in the human epidermis, hair follicles, and sebocytes. Moreover, we have shown that AEA as well as Δ9-tetrahydrocannabinol, the psychoactive product of the plant Cannabis sativa, inhibit in vitro human hair growth and induce apoptosis-driven catagen regression of the hair follicle, most probably via the cannabinoid receptor subtype 1 (CB1). Intriguingly, in human sebocytes, mostly CB2 was identified whose activation by endocannabinoids resulted in a marked stimulation of lipid synthesis and the alteration in the gene expression profile of the cells.

 

 

Figure 3. Endocannabinoids enhance lipid synthesis in    human sebocytes
a) Expression of CB2 (immunofluorescence).

b) AEA and 2-AG stimulates lipid synthesis (Nile-Red based fluorimetry). *p<0.05

Current Research Projects
Collectively, the above findings argue for that both the TRP channel(s)-coupled signaling mechanisms and the related ECS may play fundamental roles in the regulation of human cutaneous biology.

To systematically and mechanistically explore this hypothesis, in our current research projects, we aim at:
- Identifying functional roles of various TRP channels and the ECS in regulation of human cutaneous cell growth and immuno-endocrine functions in vitro (on cell and organ culture systems of keratinocytes, sebocytes, hair follicle cells, and dendritic cells) and in vivo (SCID animal models);
- Identifying novel endogenous mechanisms that regulate expressions and functions of elements of the above systems, with special emphasis on the proliferation-differentiation state of the cells and on the “endovanilloid-endocannabinoid connection”;
- Defining the relationship of TRP- and ECS-coupled signaling with other cutaneous immuno-endocrine mechanisms (e.g. the skin-equivalent of the hypothalamic – pituitary gland – target organ axis) known to be involved in regulation of skin homeostasis;
- Identifying target genes and related intracellular signalling modulated by TRP channels and the ECS;
- Determining the putative alterations of the expression patterns of TRPs and members of the ECS in various human skin diseases.

Publications: 

1) Bíró T., Maurer M., Modarres S., Lewin N. E., Brodie C, Ács G., Ács P., Paus R., and Blumberg P. M. (1998): Characterization of Functional Vanilloid Receptors Expressed by Mast Cells. Blood 91(4):1332-1340

2) Bodó E., Bíró T., Telek A., Czifra G., Griger Z., Tóth I.B., Mescalchin A., Ito T., Bettermann A., Kovács L., and Paus R. (2005): A “Hot” New Twist to Hair Biology – Involvement of Vanilloid Receptor-1 (VR1/TRPV1) Signaling in Human Hair Growth Control. Am. J. Pathol. 166(4):985-998

3) Telek A., Bíró T., Bodó E., Tóth I.B., Borbíró I., Kovács L., Kunos G., and Paus R. (2007): Inhibition of Human Hair Follicle Growth by Endo- and Exocannabinoids. FASEB J. 21(13):3534-3541

4) Tóth I.B., Géczy T., Griger Z., Dózsa A., Seltmann H., Kovács L., Nagy L., Zouboulis C.C., Paus R., and Bíró T. (2009): Transient Receptor Potential Vanilloid-1 Signaling as a Regulator of Human Sebocyte Biology. J. Invest. Dermatol. 129(2):329-339

5) Dobrosi N., Tóth I.B., Nagy G., Dózsa A., Géczy T., Nagy L., Zouboulis C.C., Paus R., Kovács L., and Bíró T. (2008): Endocannabinoids Enhance Lipid Synthesis and Apoptosis in Human Sebocytes via Cannabinoid Receptor-2-Mediated Signaling. FASEB J. 22(10):3685-3695

Recent publications – past 5 years

6) Bodó E., Kovács I., Telek A., Varga A., Paus R, Kovács L., and Bíró T. (2004): Vanilloid Receptor-1 is Widely Expressed on Various Epithelial and Mesenchymal Cell Types of Human Skin. J. Invest. Dermatol. 123(2):410-413

7) Steinhoff M., Bienenstock J., Schmelz M., Maurer M., Wei E., and Bíró T. (2006): Neurophysiological, Neuroimmunological and Neuroendocrine Basis of Pruritus. J. Invest. Dermatol. 126:1705-1718

8) Bíró T., Bodó E., Telek A., Géczy T., Tychsen B., Kovács L., and Paus R. (2006): Hair Cycle Control by Vanilloid Receptor-1 (TRPV1): Evidence from TRPV1 Knockout Mice. J. Invest. Dermatol. 126:1909-1912

9) Paus R., Schmelz M., Bíró T., and Steinhoff M. (2006): Scratching the Brain for More Effective “Itch” Therapy – Frontiers in Pruritus Research. J. Clin. Invest. 116(5):1174-1186

10) Steinhoff M. and Bíró T. (2009): A TR(I)P to Pruritus Research: Role of TRPV3 in Inflammation and Itch. J. Invest. Dermatol. 129(3):531-535