The overall goal of this proposal is to investigate the role of adenosine (ADO) in cerebral blood flow (CBF) regulation. ADO is a purine nucleoside and breakdown product of ATP via AMP. In our most recent grant, we (1) defined the ADO receptor subtype involved in vasodilation induced by ADO in vitro and during cortical activation evoked by sciatic nerve stimulation (SNS) in vivo; (2) determined that diffusion and counter current mechanisms are not involved in pial vasodilation during SNS; (3) discovered that glutamate-induced vasodilation is ADO receptor-mediated; (4) found that ADO-induced vasodilation probably involves a cGMP dependent protein kinase (PKG) and cGMP, and not cAMP-dependent protein kinase (PKA) and cAMP; (5) determined that ADO receptor manipulations during ischemia affect both brain injury and learning/memory and (6) found a novel neuroprotective effect of ADO that decreases excitatory amino acid (EAA) uptake into the brain. The present proposal will focus on the cellular and molecular mechanisms involved in ADO regulation of CBF. We will use a comprehensive multidisciplinary approach involving genetically engineered mice, in vivo and in vitro vessel preparations, cell culture, electrophysiologic, biochemical and molecular techniques.
Specific Aims : To test the following hypotheses (1) that A2B receptor activation contributes to ADO-induced and SNSinduced vasodilation, (2) that endothelial cells or vascular smooth muscle mediate ADO-induced conduction of dilator signals along cerebral arterioles, (3) that with glutamate stimulation, astrocytes are a cellular source for ADO release, (4) that in the cerebral circulation, ADO-induced vasodilation is mediated by PKG, (5) that ADO, via a receptor subtype mechanism, decreases excitatatory amino acid transport into the brain. Further investigation of ADO in brain will allow more comprehensive knowledge of the regulation of cerebral blood flow and the link between metabolism and vascular response. Such knowledge is necessary to allow more rational and innovative treatments of brain ischemia, head injury and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021076-24
Application #
7234026
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
1983-12-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2010-05-31
Support Year
24
Fiscal Year
2007
Total Cost
$559,382
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Kulik, Tobias B; Aronhime, Shimon N; Echeverry, German et al. (2010) The relationship between oxygen and adenosine in astrocytic cultures. Glia 58:1335-44
Kusano, Yoshikazu; Echeverry, German; Miekisiak, Greg et al. (2010) Role of adenosine A2 receptors in regulation of cerebral blood flow during induced hypotension. J Cereb Blood Flow Metab 30:808-15
Sehba, Fatima A; Flores, Rowena; Muller, Artur et al. (2010) Adenosine A(2A) receptors in early ischemic vascular injury after subarachnoid hemorrhage. Laboratory investigation. J Neurosurg 113:826-34
Park, Ik-Seong; Meno, Joseph R; Witt, Cordelie E et al. (2009) Impairment of intracerebral arteriole dilation responses after subarachnoid hemorrhage. Laboratory investigation. J Neurosurg 111:1008-13
Liu, Shimin; Zhen, Gehua; Meloni, Bruno P et al. (2009) RODENT STROKE MODEL GUIDELINES FOR PRECLINICAL STROKE TRIALS (1ST EDITION). J Exp Stroke Transl Med 2:2-27
Liu, Shimin (2009) Dealing with publication bias in translational stroke research. J Exp Stroke Transl Med 2:16-21
Kulik, Tobias; Kusano, Yoshikazu; Aronhime, Shimon et al. (2008) Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology 55:281-8
Miekisiak, Greg; Kulik, Tobias; Kusano, Yoshikazu et al. (2008) Cerebral blood flow response in adenosine 2a receptor knockout mice during transient hypoxic hypoxia. J Cereb Blood Flow Metab 28:1656-64
Haglund, Michael M; Meno, Joseph R; Hochman, Daryl W et al. (2008) Correlation of intrinsic optical signal, cerebral blood flow, and evoked potentials during activation of rat somatosensory cortex. J Neurosurg 109:654-63
Britz, Gavin W; Meno, Joseph R; Park, Ik-Seong et al. (2007) Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage. Stroke 38:1329-35

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