Traumatic brain injury (TBI) is reportedly the leading cause of death and disability among children and young adults (CDC Report, 2004). Among multiple sequelae, TBI results in three major pathologies: 1) cerebral edema which leads to a critical rise in intracranial pressure, 2) diffuse axonal injury which brings about disruption of neural circuits underlying cognitive and motoric behaviors, and 3) alterations in the brain's microcirculation that cause a persistent state of hypoperfusion and improper delivery of vital metabolites to neural tissue. Over 25 clinical trials aimed at the first two pathologies have been developed, none of which have been effective in the treatment for TBI. Therefore, novel studies leading to new clinical trials are necessary. To date no one has initiated a clinical trial addressing the third pathology, dysfunctional vascular reactivity following TBI. The present proposal provides rationale for proceeding towards a clinical trial by implementing novel strategies that aim to improve cerebral blood flow (CBF) and cognitive outcome following TBI. While our laboratory has published extensively on the role of endothelin-1 in mediating altered cerebral vascular reactivity after TBI, the cellular and molecular mechanism for this altered vasoreactivity remains to be elucidated. In addition the causal relationship between ET-1, altered vasoreactivity and functional outcome has not been established. This proposal addresses these issues by pharmacologic manipulation of the ET-1 system and calponin (Cp), a key element in vasoreactivity - the molecular events leading to vascular smooth muscle contractility and hence to vasoconstriction. The central hypothesis of this proposal is: TBI causes enhanced endothelin-1-mediated vasoconstriction and reduced CBF, which, in turn, exacerbates TBI-induced neuronal injury and cognitive deficits.

Public Health Relevance

Traumatic brain injury (TBI) is the leading cause of death and disability amongst our youth and children. Further, it has been named as the signature injury in the War on Terrorism that, upon return of our men and women fighting in Iraq and Afghanistan, is projected to cost millions in patient care and rehabilitation costs. While TBI results in three major pathologies, including diffuse axonal injury, brain edema, and hypoperfusion of the brain's parenchyma, this proposal investigates novel methods to increase blood flow after injury by investigating the fundamental mechanism behind hypoperfusion. In doing so, the experiments in this proposal are designed to yield results that can quickly be translated into the clinical setting, thus off-setting the current potentially dismal outcome following exposure to TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064976-03
Application #
8133700
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hicks, Ramona R
Project Start
2009-09-01
Project End
2012-03-02
Budget Start
2011-09-01
Budget End
2012-03-02
Support Year
3
Fiscal Year
2011
Total Cost
$325,850
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Shenaq, Mohammed; Kassem, Hassan; Peng, Changya et al. (2012) Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1ýý after traumatic brain injury (TBI). J Neurol Sci 323:134-40
Kreipke, Christian W; Reynolds, Christian A; Schafer, Patrick C et al. (2011) Endothelin receptors A and B are expressed in distinct cellular compartments of rat hippocampus following global ischemia: an immunocytochemical study. Neurol Res 33:162-8
Reynolds, Christian A; Kallakuri, Srinivasu; Bagchi, Mihir et al. (2011) Endothelin receptor A antagonism reduces the extent of diffuse axonal injury in a rodent model of traumatic brain injury. Neurol Res 33:192-6
Armstead, William M; Kreipke, Christian W (2011) Endothelin-1 is upregulated after traumatic brain injury: a cross-species, cross-model analysis. Neurol Res 33:133-6
Jamison, Jill T; Lewis, Monique K; Kreipke, Christian W et al. (2011) Polyadenylated mRNA staining reveals distinct neuronal phenotypes following endothelin 1, focal brain ischemia, and global brain ischemia/ reperfusion. Neurol Res 33:145-61
Higashida, Tetsuhiro; Kreipke, Christian W; Rafols, José A et al. (2011) The role of hypoxia-inducible factor-1?, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 114:92-101
Kreipke, Christian W; Rafols, José A; Reynolds, Christian A et al. (2011) Clazosentan, a novel endothelin A antagonist, improves cerebral blood flow and behavior after traumatic brain injury. Neurol Res 33:208-13
Reynolds, Christian A; Schafer, Steven; Pirooz, Ryan et al. (2011) Differential effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury. Neurol Res 33:197-200