Neural & Vascular Dysfunction As Mechanisms of Injury in Genetic Migraine Models

描述(由申请人提供)： 偏头痛通常是一种慢性进行性疾病，具有重要的激素、血管和遗传调节因素。在重要的实验进展中，已经发展了表达人类相关基因突变的偏头痛小鼠模型，以及在偏头痛先兆中涉及皮质扩散性抑制(CSD)的数据。初步数据显示，与严重和进行性偏头痛有关的基因突变的小鼠模型更容易患CSD和中风。此外，性别调节雌性突变小鼠的CSD易感性，这种易感性在性腺切除后或发情周期停止时丢失。尤其被低估的是，偏头痛更容易受到脑白质变化的影响，中风的风险更高，血管和脑实质机制对偏头痛的病理生理很重要。这项申请建议检查有关偏头痛先兆机制的重要问题，这些问题与了解头痛频率和进展增加的易感性相关(见RFA)。目的1将验证偏头痛相关突变(CaV2.1通道11A亚基和血管特异性Notch3受体中的2个突变)增加CSD易感性的假设，进一步支持CSD易感性是一种常见的病理生理机制的观点。目的1还建议测试具有两个不同基因(CaV2.1和Notch3)和CaV2.1通道中两个不同位点突变的雌性小鼠是否比雄性小鼠更容易患CSD，以及雌性小鼠增强的易感性是否与性激素有关，而不是性别特异性。AIM 2将尝试建立这些与偏头痛有关的突变与中风和脑白质损害易感性之间的联系。我们将通过新的光学成像方法(CBF、氧合作用)、放射自显影和分子应激标记来确定与CSD易感性增加相关的血管和代谢机制促进突变患者比对照患者更大的血流代谢不匹配的假设。目的3将通过测试假设进一步研究这些突变，即由遗传机制授予的CSD易感性使大脑对中风的发展更敏感，并在存在轻度缺血的情况下对脑白质损害更敏感。综上所述，这些实验旨在研究偏头痛进展的潜在机制及其神经病理后果。 偏头痛是一种非常普遍的神经疾病，临床上与中风等脑损伤风险增加有关。这项研究将有助于确定偏头痛的风险因素使个人易患中风和其他类型脑损伤的机制，并开辟新的研究途径，以预防偏头痛的这些长期、进行性和累积性并发症。

DESCRIPTION (provided by applicant): Migraine is often a chronic and progressive disorder with important hormonal, vascular and genetic modulating factors. Among the important experimental advances has been the development of mouse models of migraine expressing human mutations in implicated genes, as well as data implicating cortical spreading depression (CSD) in migraine aura. Preliminary data show that mouse models with mutations in genes implicated in severe and progressive migraine are more susceptible to CSD as well as to stroke. Furthermore, sex modulates CSD susceptibility in female mutant mice that is lost after gonadectomy or when estrus cycling ceases. Particularly underappreciated is that migraineurs are more susceptible to white matter changes and are at higher risk for stroke, and that vascular as well as brain parenchymal mechanisms are important to migraine pathophysiology. This application proposes to examine important questions about mechanisms of migraine aura that are relevant to understand the susceptibility for increasing headache frequency and progression (see RFA). Aim 1 will test the hypothesis that CSD susceptibility is increased by mutations linked to migraine (2 mutations in the 11A subunit of CaV2.1 channel, and in the blood vessel specific Notch3 receptor), further supporting the notion that CSD susceptibility is a common pathophysiological mechanism. Aim 1 also proposes to test whether female mice harboring mutations in two different genes (CaV2.1 and Notch3) and in two distinct loci in the CaV2.1 channel are more susceptible to CSD compared to males and whether enhanced susceptibility in females is sex hormone but not gender specific. Aim 2 will attempt to establish a link between these mutations implicated in migraine, and susceptibility to stroke and white matter lesions. We will test the hypothesis that vascular and metabolic mechanisms linked to increased CSD susceptibility promote greater flow- metabolism mismatch in mutants than in controls, as determined using novel optical imaging methods (CBF, oxygenation), autoradiography, and molecular stress markers. Aim 3 will further study these mutations by testing the hypothesis that CSD susceptibility conferred by genetic mechanisms renders the brain more sensitive to the development of stroke, and of white matter lesions in the presence of mild ischemia. Taken together these experiments are intended to examine mechanisms underlying progression of migraine and its neuropathological consequences. Migraine is a highly prevalent neurological disorder that is clinically associated with increased risk of brain injury such as stroke. This research will help identify the mechanisms by which risk factors for migraine predispose individuals to stroke and other types of brain injury, and open new avenues of research to prevent these long term progressive and cumulative complications of migraine.