Inflammation appears to play a critical role in the formation of cerebral aneurysms, their progression to rupture- prone type, and ultimately to rupture. Evidence supporting this hypothesis includes recent data from human neurosurgery patients and experimental animal models demonstrating that aneurysm wall tissue is rich with macrophages and inflammatory molecules. To investigate potential therapeutic implications of this hypothesis, I carried out a retrospective study examining whether patients with unruptured cerebral aneurysms who took aspirin had a reduced risk of aneurysm rupture. This study was performed using the International Study of Unruptured Intracranial Aneurysms data base. Patients who used aspirin three times weekly to daily had a significantly decreased risk of aneurysm rupture. My current scientific goals, and the subject of this proposal, are to study the molecular mechanisms by which inflammation influences cerebral aneurysm formation and rupture. I am using the well-established Hashimoto mouse aneurysm model to pursue two specific aims.
In Specific Aim 1, I will determine the contributions of COX-1 and COX-2 to the protective effect of aspirin against aneurysm rupture.
In Specific Aim 2, I will determine the cell type associated with activation of the COX-2 pathway resulting in a protective effect against aneurysm rupture. These studies will involve the use of complementary genetic, pharmacological and bone marrow transplantation experimental approaches. Knowledge of the inflammation related molecular mechanisms of aneurysm formation and rupture will provide information that is critical to the development of effective new medical therapies for patients with this dangerous cerebrovascular disease.

Public Health Relevance

The primary goal of the proposed project is to delineate molecular mechanisms of the protective effect of aspirin in reducing the incidence of cerebral aneurysm rupture using an experimental animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS082363-01A1
Application #
8634915
Study Section
NST-2 Subcommittee (NST)
Program Officer
Koenig, James I
Project Start
2013-09-30
Project End
2018-08-31
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$167,886
Indirect Cost
$12,436
Name
University of Iowa
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Chalouhi, Nohra; Starke, Robert M; Correa, Tatiana et al. (2016) Differential Sex Response to Aspirin in Decreasing Aneurysm Rupture in Humans and Mice. Hypertension 68:411-7
Peña-Silva, Ricardo A; Chalouhi, Nohra; Wegman-Points, Lauren et al. (2015) Novel role for endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms. Hypertension 65:587-93
Hoppe, Anna L; Raghavan, Madhavan L; Hasan, David M (2015) Comparison of the association of sac growth and coil compaction with recurrence in coil embolized cerebral aneurysms. PLoS One 10:e0123017
Chu, Yi; Wilson, Katina; Gu, He et al. (2015) Myeloperoxidase is increased in human cerebral aneurysms and increases formation and rupture of cerebral aneurysms in mice. Stroke 46:1651-6
Hasan, David M; Hindman, Bradley J; Todd, Michael M (2015) Pressure changes within the sac of human cerebral aneurysms in response to artificially induced transient increases in systemic blood pressure. Hypertension 66:324-31
Hasan, David M; Starke, Robert M; Gu, He et al. (2015) Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo. Hypertension 66:211-20
Peña Silva, Ricardo A; Mitchell, Ian J; Kung, David K et al. (2015) Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin. Neurosurgery 77:613-20
Starke, Robert M; Chalouhi, Nohra; Ding, Dale et al. (2015) Potential role of aspirin in the prevention of aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 39:332-42
Tada, Yoshiteru; Makino, Hiroshi; Furukawa, Hajime et al. (2014) Roles of estrogen in the formation of intracranial aneurysms in ovariectomized female mice. Neurosurgery 75:690-5; discussion 695
Tada, Yoshiteru; Wada, Kosuke; Shimada, Kenji et al. (2014) Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension 63:1339-44

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