The Role of Mast Cells in the Pathophysiology of Intracranial Aneurysm

描述(申请人提供)：动脉瘤性破裂引起的蛛网膜下腔出血会导致严重的发病率和高死亡率。未破裂的颅内动脉瘤的治疗仍然存在争议。用药物稳定动脉瘤以预防动脉瘤破裂可能是外科手术或血管内治疗的一种有吸引力的替代治疗方法。我们开发了一种新的小鼠颅内动脉瘤模型。在这个模型中，自发性动脉瘤样破裂的发生有一个可预测的时间过程。在这个模型中，通过评估神经症状可以很容易地检测到动脉瘤破裂。这一模型为我们研究动脉瘤破裂的机制和药物预防提供了一个独特的机会。我们有非常令人兴奋的动物研究数据表明，虽然肥大细胞在动脉瘤的形成中不是关键，但肥大细胞在动脉瘤破裂的发展中起着重要的作用。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，并且肥大细胞和肥大细胞衍生的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理稳定性是否可以预防动脉瘤破裂，以及肥大细胞的药理激活是否促进动脉瘤破裂。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是确定缺乏肥大细胞是否可以预防动脉瘤破裂。我们假设，肥大细胞的缺乏可以降低破裂率，而不会影响动脉瘤的总体发生率。我们将利用肥大细胞遗传缺陷的小鼠，KitW-sh/W-sh小鼠。目的3确定肥大细胞衍生的细胞因子在促进肥大细胞促进动脉瘤破裂中的作用。我们假设肥大细胞糜酶是促进动脉瘤破裂的主要肥大细胞来源的细胞因子。我们将测试使用糜酶基因敲除小鼠的骨髓来源的肥大细胞重建是否无法将KitW-sh/W-sh小鼠的破裂率恢复到野生型小鼠的水平。我们还将通过从缺乏白细胞介素6、肿瘤坏死因子-α或干扰素-γ的小鼠的骨髓来源的肥大细胞重建KitW-sh/W-sh小鼠的肥大细胞群来评估其他肥大细胞来源的细胞因子的贡献。这些研究代表了研究动脉瘤破裂机制的新努力。这些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。这项研究将成为未来研究的基础，以测试针对肥大细胞或肥大细胞衍生细胞因子的药物治疗，以预防动脉瘤性蛛网膜下腔出血。

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.