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和进行性疾病，具有重要的激素、血管和遗传调节因素。其中重要的实验进展是偏头痛小鼠模型的发展，在相关基因中表达人类突变，以及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CSD的易感性，在雌性突变小鼠后，性腺切除或发情周期停止时丢失。尤其是偏头痛患者更易受白色物质变化的影响，并且中风的风险更高，并且血管和脑实质机制对偏头痛的病理生理学很重要。本申请旨在研究偏头痛先兆机制的重要问题，这些问题与了解头痛频率增加和进展的易感性有关（见RFA）。目的1将检验CSD易感性通过与偏头痛相关的突变（CaV2.1通道的11 A亚基和血管特异性Notch 3受体中的2个突变）增加的假设，进一步支持CSD易感性是常见病理生理机制的观点。目的1还提出测试在两个不同的基因（CaV2.1和Notch 3）和CaV2.1通道中的两个不同的基因座中携带突变的雌性小鼠是否比雄性小鼠更容易受到CSD的影响，以及女性易感性的增强是否是性激素而不是性别特异性的。目标2将试图建立这些突变与偏头痛、中风易感性和白色病变之间的联系。我们将检验这一假设，即与CSD易感性增加相关的血管和代谢机制促进突变体比对照组更大的流量-代谢失配，如使用新型光学成像方法（CBF，氧合），放射自显影和分子应激标记物所确定的。目的3将进一步研究这些突变，通过检验以下假设：遗传机制赋予的CSD易感性使大脑对中风和轻度缺血时的白色病变的发展更敏感。总之，这些实验旨在研究偏头痛及其神经病理学后果进展的机制。 偏头痛是一种高度流行的神经系统疾病，临床上与脑损伤（如中风）的风险增加相关。这项研究将有助于确定偏头痛的危险因素使个体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.