(Verbatim from the application): The regulation of cerebral blood flow occurs primarily at the blood vessel-brain parenchyma interface and depends on a complex array of chemical and electrical stimuli that, under physiologic conditions, couple cerebral blood flow to neuronal activity. It has been proposed that potassium ions lost by neuronal cells during action potential repolarization may affect vessel diameter by acting on inward rectifier channel mechanisms expressed in vascular smooth muscle cells. We have recently demonstrated a novel mechanism of potassium-induced vasodilatation that implies activation of """"""""metabolic channels,"""""""" normally shut down by intracellular ATP (K(ATP)). We propose to investigate in detail the relevance of such a mechanism in vitro and in vivo. In addition, we and others have shown that expression of potassium channels involved in the regulation of cerebral blood flow and in the control of extracellular ion homeostasis are compromised following traumatic brain injury or ischemia. We therefore propose to investigate how the loss of these mechanisms can impact cerebrovascular function in neurological disease. The underlying hypothesis of this proposal is that, in the brain, activation of K(ATP) not only mediates changes caused by oxygen deprivation, but is also responsible for potassium-mediated vasodilatations occurring during normal oxygen supply and therefore during normal neuronal activity.
The Specific Aims of our proposals are: 1) To investigate in vitro the ion channel mechanisms involved in potassium-mediated vasodilatation. 2) To elucidate the mechanisms of potassium-mediated dilations in vivo. These studies will allow better understanding on neuronal-vascular interactions and will open new perspectives for the treatment of neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051614-07
Application #
6389326
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
1994-01-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
7
Fiscal Year
2001
Total Cost
$296,000
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Cucullo, Luca; Hossain, Mohammed; Puvenna, Vikram et al. (2011) The role of shear stress in Blood-Brain Barrier endothelial physiology. BMC Neurosci 12:40
Cucullo, Luca; Marchi, Nicola; Hossain, Mohammed et al. (2011) A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system. J Cereb Blood Flow Metab 31:767-77
Marchi, Nicola; Betto, Giulia; Fazio, Vincent et al. (2009) Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema. Epilepsia 50:664-77
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Cucullo, Luca; Couraud, Pierre-Olivier; Weksler, Babette et al. (2008) Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies. J Cereb Blood Flow Metab 28:312-28
Marchi, Nicola; Mazzone, Peter; Fazio, Vincent et al. (2008) ProApolipoprotein A1: a serum marker of brain metastases in lung cancer patients. Cancer 112:1313-24
Marchi, Nicola; Oby, Emily; Batra, Ayush et al. (2007) In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia 48:1934-46
Cucullo, Luca; Hossain, Mohammed; Rapp, Ed et al. (2007) Development of a humanized in vitro blood-brain barrier model to screen for brain penetration of antiepileptic drugs. Epilepsia 48:505-16
Hallene, K L; Oby, E; Lee, B J et al. (2006) Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations. Neuroscience 142:267-83

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