Prof. Dr. Kuyaş BUĞRA

Boğaziçi Üniversitesi
Moleküler Biyoloji ve Genetik
Kuzey Park, 303
34342 Bebek - Istanbul
+90 (212) 359 7158
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FGF-signaling in retinal Müller cells

The major research focus of my laboratory is to explore FGF signaling in the context of retinal Müller cell biology. Müller glial cells are well known for their roles in tissue homeostasis and for their trophic support of neurons. Like other glia of the CNS, Müller cells undergo a series of changes upon injury, hypoxia and disease states like diabetic retinopathy and glaucoma. These changes, named reactive gliosis, involve altered gene expression and enhanced proliferation. Though gliosis is thought to be an attempt to keep the tissue homeostasis, it often contributes to retinal pathology. In addition to homeostatic roles, at least a subpopulation of Müller cells have potential to transdifferentiate to neurons upon injury to replace the lost ones.

FGF2 is one of the factors known to enhance proliferation of Müller cells. We and others have shown that this response is elicited via activation of Erk1/2, and to a smaller extent, Akt pathways. Our recent studies indicated that the serine/threonine kinase SIK2 is an integral part of FGF signal transduction in these cells and led us to propose that SIK2 acts as an element of a feedback mechanism in fine-tuning of Erk and Akt activation through Gab1.

In the framework of our working model, we are pursuing the following projects:

  • Project 1 aim to explore whether SIK2 is implicated in transdifferentiation of Müller cells. We are using a human Müller cell line MIO-M1, a kind gift of Dr. Astrid Limb (University College London), which can be induced to express first progenitor, then neuronal markers by prolonged exposure to FGF2.

  • Project 2 involves further investigation of SIK2 interactions with the pathway elements. These studies focus mainly on Erk1/2 as a potential upstream kinase of SIK2 and identification of SIK2-Gab1 interaction domains.

  • Project 3 involves probing into the possibility of SIK2 being a tumor suppressor protein. Particularly in breast cancers levels of this kinase is significantly downregulated. We are currently investigating the effect of modulations in SIK2 expression in tumorigenic capacity of breast cancer cell lines. In parallel primary tumors are being screened for mutations in SIK2 gene.

  • Project 4 is an expansion of our in vitro studies suggesting SIK2 as a negative regulator of insulin-dependent Müller cell survival via IRS1/Akt axis. In this study potential contribution of SIK2 to development of diabetic retinopathy is investigated in experimental models of the disease.

Seçilmiş Yayınlar

  • Alkan C, Kavak P, Somel M, Gokcumen O, Ugurlu S, Saygi C, Dal E, Bugra K, Güngör T, Sahinalp SC, Özören N, Bekpen C (2014) Whole genome sequencing of Turkish genomes reveals functional private alleles and impact of genetic interactions with Europe, Asia and Africa.
    BMC Genomics 15:963. doi: 10.1186/1471-2164-15-963.

  • Küser-Abali G, Ozcan F, Ugurlu A, Uysal A, Fuss SH, Bugra-Bilge K (2013) SIK2 is involved in the negative modulation of insulin-dependent muller cell survival and implicated in hyperglycemia-induced cell death.
    Invest Ophthalmol Vis Sci. 54(5):3526-37. doi: 10.1167/iovs.12-10729.

  • Siffroi-Fernandez S, Cinaroglu A, Fuhrmann-Panfalone V, Normand G, Bugra K, Sahel J, Hicks D (2005) Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma.
    Arch Ophthalmic. 123(3):368-76.

  • Cinaroglu A, Ozmen Y, Ozdemir A, Ozcan F, Ergorul C, Cayirlioglu P, Hicks D, Bugra K (strong>(2005) Expression and possible function of fibroblast growth factor 9 (FGF9) and its cognate receptors FGFR2 and FGFR3 in postnatal and adult retina.
    J Neurosci Res 79(3):329-39.