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

神经

• 批准号: 7407285
• 负责人: Cenk Ayata
• 金额: $ 38.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407285
• 关键词: Abbreviations; Area; Arts; Auras; Autoradiography; Biological Markers; Blood Circulation; Blood Vessels; Brain; Brain Injuries; CADASIL; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Condition; Data; Deoxyglucose; Development; Disease; Disease model; Electrophysiology (science); Estrus; Exhibits; Familial Hemiplegic Migraine; Female; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Gender; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Glucose; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Headache; Hemiplegia; Hormonal; Human; Hypoxia; Individual; Infarction; Injection of therapeutic agent; Injury; Ischemia; Knock-in Mouse; Lead; Lesion; Link; Metabolic; Metabolism; Methods; Migraine; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurologic; Neurons; Oxygen; P-Q type voltage-dependent calcium channel; Patent Foramen Ovale; Patients; Phenotype; Physiological; Play; Point Mutation; Predisposition; Progressive Disease; Proteins; Rate; Research; Risk; Risk Factors; Role; Secondary to; Sex Characteristics; Spreading Cortical Depression; Stress; Stroke; Technology; Testing; Tissue Viability; Tissues; Transgenic Organisms; Vascular Endothelial Growth Factors; aged; base; cerebral hypoperfusion; clinically relevant; design; human disease; hypoxia inducible factor 1; iodoantipyrine; male; mouse model; mutant; nervous system disorder; novel; optical imaging; prevent; receptor; relating to nervous system; research study; sex; tool; voltage; white matter; white matter change

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.

描述（由申请人提供）： 偏头痛通常是一种慢性进行性疾病，与重要的激素、血管和遗传调节因素有关。重要的实验进展包括开发了表达人类相关基因突变的偏头痛小鼠模型，以及偏头痛先兆中皮质扩散抑制（CSD）的数据。初步数据显示，具有与严重和进行性偏头痛相关的基因突变的小鼠模型更容易患慢性病（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消失。尤其被低估的是，偏头痛患者更容易受到白质变化的影响，并且中风的风险更高，而血管和脑实质机制对于偏头痛的病理生理学很重要。本申请旨在研究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增加和进展的易感性相关（参见 RFA）。目标 1 将检验以下假设：与偏头痛相关的突变（CaV2.1 通道的 11A 亚基和血管特异性 Notch3 受体中的 2 个突变）会增加 CSD 易感性，进一步支持 CSD 易感性是一种常见病理生理学的观点。机制。目标 1 还建议测试在两个不同基因（CaV2.1 和 Notch3）以及 CaV2.1 通道中两个不同基因座中携带突变的雌性小鼠是否比雄性更容易患 CSD，以及雌性小鼠易感性的增强是否与性激素有关但不分性别。目标 2 将尝试建立这些与偏头痛有关的突变与中风和白质病变的易感性之间的联系。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会导致突变体比对照组更大的血流代谢失配，这一点是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确定的。目标 3 将通过测试以下假设来进一步研究这些突变：遗传机制赋予的 CSD 易感性使大脑对中风的发展以及轻度缺血时的白质病变更加敏感。总的来说，这些实验旨在研究偏头痛进展的机制及其神经病理学后果。 偏头痛是一种非常普遍的神经系统疾病，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来预防偏头痛的这些长期进行性和累积性并发症。