The Role of Mast Cells in the Pathophysiology of Intracranial Aneurysm

描述（申请人提供）：动脉瘤破裂引起的蛛网膜下腔出血，发病率高，死亡率高。未破裂颅内动脉瘤的治疗仍有争议。药物稳定动脉瘤预防动脉瘤破裂可能是一个有吸引力的替代方法手术或血管内的途径。我们开发了一种新的小鼠颅内动脉瘤模型。在该模型中，自发性动脉瘤破裂的发生具有可预测的时间过程。在这个模型中，动脉瘤破裂可以很容易地通过评估神经症状来检测。这个模型为我们提供了一个独特的机会来研究动脉瘤破裂的机制以及药物预防。我们有非常令人兴奋的动物研究数据表明，尽管肥大细胞对动脉瘤的形成并不重要，但肥大细胞在动脉瘤破裂的发展中起着重要作用。此外，我们对人类动脉瘤标本的初步研究表明，破裂的动脉瘤比未破裂的动脉瘤有更多的肥大细胞。因此，我们假设肥大细胞在动脉瘤破裂中起关键作用，肥大细胞和肥大细胞源性细胞因子可以作为预防动脉瘤破裂的治疗靶点。目的1是确定肥大细胞的药物稳定是否可以防止动脉瘤破裂，肥大细胞的药物激活是否可以促进动脉瘤破裂。我们假设肥大细胞释放的细胞因子促进了动脉瘤破裂。目的2是确定肥大细胞的缺乏是否可以防止动脉瘤破裂。我们假设肥大细胞的缺乏降低了破裂率而不影响动脉瘤的总体发生率。我们将使用肥大细胞基因缺陷的小鼠，KitW-sh/W-sh小鼠。目的3是鉴定肥大细胞衍生的细胞因子，该细胞因子负责肥大细胞促进动脉瘤破裂。我们假设肥大细胞切酶是促进动脉瘤破裂的主要肥大细胞源性细胞因子。我们将测试使用切酶敲除小鼠骨髓来源的肥大细胞重建肥大细胞是否不能将KitW-sh/W-sh小鼠的破裂率恢复到野生型小鼠的水平。我们还将评估其他肥大细胞源性细胞因子的贡献，通过缺乏白细胞介素-6、肿瘤坏死因子- α或干扰素- γ的小鼠骨髓源性肥大细胞重建KitW-sh/W-sh小鼠的肥大细胞群。这些研究代表了研究动脉瘤破裂机制的新努力。结果将为肥大细胞在动脉瘤破裂中的独特作用提供新的见解。这项研究将为未来研究测试针对肥大细胞或肥大细胞源性细胞因子的药物治疗预防动脉瘤性蛛网膜下腔出血奠定基础。

DESCRIPTION (provided by applicant): 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.