Glial tumors carry very poor prognosis due to their rapid growth and invasive migration. The mechanism(s) that trigger glial growth, especially those leading to increased proliferation, could be important for treatment;however, they remain largely unknown. The survival of patients with glioblastoma multiforme, for example, is on average 12 months, despite most aggressive treatments, and this prognosis has remained unchanged for the past 30 years. Therefore, new approaches are required to address this problem. This project proposes to test a novel hypothesis that involves the interaction of two ion channels: the large conductance calcium- and voltage-activated potassium channels (BK) and acid-sensing ion channels (ASICs). BKs are expressed in normal glial cells and in gliomas and have been shown to potentiate cell proliferation;their blockers inhibit glioma cell growth. Functional regulation of BK channel activity could contribute to glial proliferation. Both normal glia and glioma tissues express ASICs that inhibit BKs in a pH-dependent manner, and the expression of ASICs changes with the progression of the tumor. ASICs therefore could act as endogenous inhibitors of BK and related glial growth, until a drop in the extracellular pH (during brain injury, trauma, stroke) leads to the relief of this inhibition. Then, a more active BK promotes glial growth and proliferation. To test the hypothesis that dysregulation of ASIC-BK interaction leads to increased proliferation of glia, the following specific aims are proposed: 1) to determine the molecular mechanisms involved in ASIC1a-BK interaction in glial cells;2) to determine the effects of ASIC1a-BK interaction on cell growth, proliferation, and migration. This proposal represents a unique opportunity for an undergraduate and a master's student to perform experiments in the area of glial and tumor growth in a real research lab setting. The students, under the guidance of the principal investigator, will perform this small-scale research project that will yield important data. The project will provide laboratory training and research experience, and prepare the students for future graduate work and careers in biomedical science. The estimated duration of this project is three years.
Glial tumors carry very poor prognosis due to their rapid growth. The survival of patients with glioblastoma multiforme, for example, is an average of 12 months, and this prognosis has remained unchanged for the past 30 years. New approaches are required to address this problem. This project proposes to test a novel hypothesis that acidosis-dependent regulation of the large conductance calcium- and voltage-activated potassium channels that promote glial growth, by their endogenous blockers, acid-sensing ion channels, could contribute to glial proliferation. This proposal represents a unique opportunity for an undergraduate and a master's student to perform experiments in the area of glial growth and potential tumorogenesis, to contribute to scientific knowledge and to our efforts to fight this devastating disease.
|Excoffon, Katherine J D A; Kolawole, Abimbola O; Kusama, Nobuyoshi et al. (2012) Coxsackievirus and adenovirus receptor (CAR) mediates trafficking of acid sensing ion channel 3 (ASIC3) via PSD-95. Biochem Biophys Res Commun 425:13-8|
|Petroff, Elena; Snitsarev, Vladislav; Gong, Huiyu et al. (2012) Acid sensing ion channels regulate neuronal excitability by inhibiting BK potassium channels. Biochem Biophys Res Commun 426:511-5|