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

神经

• 批准号: 8213639
• 负责人: Cenk Ayata
• 金额: $ 35.75万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213639
• 关键词: Area; Auras; Autoradiography; Biological Markers; Blood Vessels; Brain; Brain Injuries; CADASIL; Cerebral Ischemia; Cerebrovascular Circulation; Chronic; Clinical; Data; Deoxyglucose; Development; Disease; Disease model; Electrophysiology (science); Estrus; Exhibits; Familial Hemiplegic Migraine; Female; Frequencies; Functional disorder; Gender; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Gonadal Hormones; Gonadal Steroid Hormones; Headache; Hemiplegia; Hormonal; Human; Hypoxia; Individual; Infarction; Injection of therapeutic agent; Injury; Ischemia; Knock-in Mouse; Lead; Lesion; Letters; Link; Metabolic; Metabolism; Migraine; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Names; Neurologic; Neurons; P-Q type voltage-dependent calcium channel; Patients; Phenotype; Physiological; Point Mutation; Predisposition; Principal Investigator; Progressive Disease; Proteins; Research; Resource Sharing; Risk; Risk Factors; 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; high risk; human disease; hypoxia inducible factor 1; imaging modality; male; mouse model; mutant; nervous system disorder; novel; optical imaging; prevent; programs; receptor; relating to nervous system; research study; sex; tool; treatment strategy; white matter; white matter change; Area; Auras; Autoradiography; Biological Markers; Blood Vessels; Brain; Brain Injuries; CADASIL; Cerebral Ischemia; Cerebrovascular Circulation; Chronic; Clinical; Data; Deoxyglucose; Development; Disease; Disease model; Electrophysiology (science); Estrus; Exhibits; Familial Hemiplegic Migraine; Female; Frequencies; Functional disorder; Gender; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Gonadal Hormones; Gonadal Steroid Hormones; Headache; Hemiplegia; Hormonal; Human; Hypoxia; Individual; Infarction; Injection of therapeutic agent; Injury; Ischemia; Knock-in Mouse; Lead; Lesion; Letters; Link; Metabolic; Metabolism; Migraine; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Names; Neurologic; Neurons; P-Q type voltage-dependent calcium channel; Patients; Phenotype; Physiological; Point Mutation; Predisposition; Principal Investigator; Progressive Disease; Proteins; Research; Resource Sharing; Risk; Risk Factors; 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; high risk; human disease; hypoxia inducible factor 1; imaging modality; male; mouse model; mutant; nervous system disorder; novel; optical imaging; prevent; programs; receptor; relating to nervous system; research study; sex; tool; treatment strategy; 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和进行性疾病，具有重要的激素，血管和遗传调节因素。重要的实验进步之一是开发了偏头痛的小鼠模型，这些模型表达了含义的基因中的人类突变，以及暗示偏头痛偏头痛抑郁症（CSD）的数据。初步数据表明，与严重和进行性偏头痛有关的基因中具有突变的小鼠模型更容易受到CSD和中风的影响。此外，性别可调节雌性突变小鼠的CSD敏感性，后者在促性腺切除术后丢失或发情骑自行车停止时。尤其是不足以证明的是，偏头痛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。该应用程序建议检查有关偏头痛机制的重要问题，这些问题与了解增加头痛频率和进展的易感性相关（请参阅RFA）。 AIM 1将通过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11a个突变）提高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。 AIM 1还建议测试在两个不同基因（CAV2.1和Notch3）中携带突变的雌性小鼠，而在Cav2.1通道中的两个不同基因座中，与男性相比，CSD更容易受到CSD的影响，并且女性的易感性增强是性激素的，而不是性别激素。 AIM 2将尝试建立与偏头痛有关的这些突变与中风和白质病变的敏感性之间的联系。我们将检验以下假设：与对照组相比，与CSD易感性提高相关的血管和代谢机制可促进更大的流动代谢不匹配，这是使用新型光学成像方法（CBF，氧化），自动摄影术和分子应力标记确定的。 AIM 3将通过测试以下假设，即遗传机制赋予的CSD敏感性使大脑对中风的发展和白质病变更敏感，这将进一步研究这些突变。综上所述，这些实验旨在检查偏头痛进展及其神经病理学后果的机制。 偏头痛是一种高度普遍的神经系统疾病，在临床上与脑损伤（例如中风）的风险增加有关。这项研究将有助于确定偏头痛个体中风和其他类型的脑损伤的风险因素的机制，以及开放研究的新途径，以防止偏头痛的长期进行性和累积并发症。