Subarachnoid hemorrhage resulting from aneurysmal rupture causes severe morbidity and high mortality. The management of unruptured intracranial aneurysms remains controversial. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture may be an attractive alternative approach to surgical or endovascular approaches. We have developed a novel mouse model of intracranial aneurysm. In this model, spontaneous aneurysmal rupture occurs with a predictable time course. Aneurysmal rupture in this model can be easily detected by assessing neurological symptoms. This model provides us a unique opportunity to study the mechanisms of aneurysmal rupture as well as pharmacological prevention. We have very exciting animal study data suggesting that while mast cells are not critical for the formation of aneurysms, mast cells play a significant role in te development of aneurysmal rupture. In addition, our pilot study using human aneurysm specimens indicates that ruptured aneurysms have a higher number of mast cells than unruptured aneurysms. Therefore, we hypothesize that mast cells play critical roles in aneurysmal rupture and that mast cells and mast cell-derived cytokines can be therapeutic targets for the prevention of aneurysmal rupture.
Aim 1 is to determine whether pharmacological stabilization of mast cells protects against aneurysmal rupture and whether pharmacological activation of mast cells promotes aneurysmal rupture. We hypothesize that the release of cytokines from mast cells promotes aneurysmal rupture.
Aim 2 is to determine whether a lack of mast cells protects against aneurysmal rupture. We hypothesize that a lack of mast cells reduces a rupture rate without affecting the overall incidence of aneurysms. We will utilize the mice that are genetically deficient in mast cells, KitW-sh/W-sh mice.
Aim 3 is to identify the mast cell-derived cytokine that is responsible for the promotion of aneurysmal rupture by mast cells. We hypothesize that mast cell chymase is the primary mast cell-derived cytokine that promotes aneurysmal rupture. We will test whether the mast cell reconstitution using bone marrow-derived mast cells from chymase knockout mice will fail to restore the rupture rate of KitW-sh/W-sh mice to the level observed in wild-type mice. We will also assess contributions from other mast cell-derived cytokines by reconstituting the mast cell population in KitW-sh/W-sh mice by bone marrow-derived mast cells from mice lacking interleukin-6, tumor necrosis factor-alpha, or interferon-gamma. These studies represent novel efforts to study the mechanisms of aneurysmal rupture. Results will provide new insights into the unique roles of mast cells in aneurysmal rupture. This study will be a basis for future studies to test pharmacological therapies that target mast cells or mast cells-derived cytokines for the prevention of aneurysmal subarachnoid hemorrhage.

Public Health Relevance

Utilizing a unique mouse model of intracranial aneurysm, we will test the hypothesis that mast cells play critical roles in aneurysmal rupture and that mast cells can be a therapeutic target for the prevention of aneurysmal rupture. This proposal represents a novel effort to directly study mechanisms of aneurysmal rupture. This study will be a basis for future pharmacological therapies that target mast cells or mast cells-derived chemokines for the prevention of aneurysmal subarachnoid hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS082280-01A1
Application #
8630058
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$343,802
Indirect Cost
$125,052
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tada, Yoshiteru; Wada, Kosuke; Shimada, Kenji et al. (2014) Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:579-86
Tada, Yoshiteru; Wada, Kosuke; Shimada, Kenji et al. (2014) Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension 63:1339-44
Wada, Kosuke; Makino, Hiroshi; Shimada, Kenji et al. (2014) Translational research using a mouse model of intracranial aneurysm. Transl Stroke Res 5:248-51
Takayanagi, Takehiko; Crawford, Kevin J; Kobayashi, Tomonori et al. (2014) Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase. Clin Sci (Lond) 126:785-94