During the previous funding period we showed that glioma cells shrink as they invade the narrow extracellular spaces in the brain. Cell shrinkage is energetically driven by K+ and Cl- efflux through ion channels, which osmotically drives water out of the cell. We identified the underlying Cl-, and Ca2+-activated K+ channels and demonstrated that their pharmacological inhibition renders glioma cells unable to invade. One of the underlying channels, ClC-3, is regulated by chlorotoxin, a scorpion-derived peptide that inhibits Cl- currents and retards glioma invasion. These finding led us to initiate a Phase I/II clinical trial examining chlorotoxin as an anti-tumor drug in patients with malignant glioma which is now in Phase II. This competitive renewal application expands on unexpected observations made that mechanistically link Cl- movement to cell volume changes that occur in the context of cell proliferation and terminal cell proliferation, i.e. apoptosis. Specifically we hypothesize that glioma cells maintain elevated intracellular Cl- through active ion transport, which in turn allows cells to release Cl- through channels as they condense to enter mitosis. Cell shrinkage is directly caused by Cl- efflux and its inhibition inhibits proliferation. It also prevents condensation preceding apoptosis. Following each cell division cells re- establish their original volume through transport mediated Cl-/K+ and water uptake, which again is a necessary step for cell growth.
4 Specific aims are proposed that study the underlying Cl- channels and transporters, their mechanistic role in cell volume changes associated with proliferation and apoptosis as well as their regulation by phosphorylation and membrane trafficking. Finally, two FDA approved Cl- transport inhibitors will be examined preclinically using an animal model for malignant glioma.

Public Health Relevance

This competitive renewal application expands on unexpected observations made that mechanistically link Cl- movement to cell volume changes that occur in the context of cell proliferation and terminal cell proliferation, i.e. apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036692-13
Application #
8243576
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Fountain, Jane W
Project Start
1997-08-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$310,844
Indirect Cost
$96,469
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Campbell, Susan L; Robel, Stefanie; Cuddapah, Vishnu A et al. (2015) GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 63:23-36
Turner, Kathryn L; Sontheimer, Harald (2014) Cl- and K+ channels and their role in primary brain tumour biology. Philos Trans R Soc Lond B Biol Sci 369:20130095
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Seifert, Stefanie; Sontheimer, Harald (2014) Bradykinin enhances invasion of malignant glioma into the brain parenchyma by inducing cells to undergo amoeboid migration. J Physiol 592:5109-27
Robert, Stephanie M; Ogunrinu-Babarinde, Toyin; Holt, Kenneth T et al. (2014) Role of glutamate transporters in redox homeostasis of the brain. Neurochem Int 73:181-91
Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F et al. (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196
Turner, Kathryn L; Honasoge, Avinash; Robert, Stephanie M et al. (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62:971-81

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