Little is known about intracranial aneurysm (IA) formation. We submit that specific hemodynamic conditions, not evaluated in prior aneurysm models, are critical for IA formation. Using a rabbit IA model, this project seeks to define these specific hemodynamic conditions responsible for aneurysm initiation and to identify key molecular responses in the pathological vascular remodeling that initiates aneurysms. We hypothesize that: 1) unusual hemodynamics at cerebrovascular bifurcations that is characterized by high wall shear stress (WSS) and wall shear stress gradient (WSSG) induces aneurysmal destructive remodeling, and 2) this pathological response is mediated by localized hemodynamic stimulation of nitric oxide (NO) production and matrix metalloproteinase (MMP) activity. We will evaluate the dose-dependence of this hemodynamic initiation of IAs and use computational fluid dynamics (CFD) to map the initiating hemodynamics. This will define the specific hemodynamic conditions responsible for inducing BT aneurysms, and allow subsequent experiments to examine the biological responses to IA-initiating hemodynamics that precede aneurysm formation. We will then examine hemodynamically induced changes in nitric oxide production and MMP activity during this early period of aneurysm initiation. The roles of NO and MMP in hemodynamic induction of IAs will be tested via pharmacological manipulation of these molecules.
Aim 1. Determine specific hemodynamic conditions responsible for flow-induced IA initiation.
Aim 2. Determine the role of MMPs in hemodynamic initiation of IAs.
Aim 3. Determine the role of iNOS in regulating hemodynamic initiation of IAs. Significance: IA rupture is associated with devastating consequences for patients with high mortality and morbidity. IA formation remains poorly understood. Elucidating the role of specific hemodynamics in IA initiation will pave the way for new mechanistic understandings of IA growth and possibly rupture.

Public Health Relevance

Intracranial aneurysms have catastrophic consequences with high morbidity and mortality if they rupture. What causes intracranial aneurysms to develop is unclear, but blood flow (hemodynamics) conditions play an important role. This study seeks to elucidate the specific hemodynamic and biological mechanisms involved in initiating intracranial aneurysms in order to pave the way for improved diagnostic and prognostic capabilities and the development of more effective prevention strategies and less invasive therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064592-04
Application #
8265891
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2009-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$339,784
Indirect Cost
$125,409
Name
State University of New York at Buffalo
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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