Etiological Role of Parasitic Exposure and Familial Susceptibility in Nodding Syndrome-Related Epilepsies

寄生虫暴露和家族易感性在点头综合征相关癫痫中的病因学作用

• 批准号: 10706332
• 负责人: Rajarshi Mazumder
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706332
• 关键词: Affect; Africa South of the Sahara; African; Antibodies; Antigens; Antiparasitic Agents; Autoimmunity; Blood; Board Certification; Brain Diseases; California; Child; Clinical; Communities; Convulsions; Country; DNA; Data; Development Plans; Disease; Drops; Early identification; Economic Burden; Electroencephalography; Electrophysiology (science); Environmental Risk Factor; Epilepsy; Epileptogenesis; Etiology; Evaluation; Exposure to; Family; Family member; Foundations; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Grant; Head; High Prevalence; Household; Human; Immune response; Impaired cognition; Incidence; Income; Individual; Interview; Intestinal Volvulus; Lead; Los Angeles; Mentors; Modeling; Molecular Epidemiology; Molecular Mimicry; Muscle; Onchocerca volvulus; Onchocerciasis; Parasites; Parasitic Diseases; Parents; Participant; Pathogenesis; Persons; Phenotype; Predisposition; Prevalence; Preventive measure; Primary Prevention; Proteins; Research; Research Design; Research Personnel; Resource-limited setting; Resources; Risk; Role; Second Degree Relative; Seizures; Serum; Siblings; Standardization; Syndrome; Testing; Time; Training; Tribes; Uganda; United States; Universities; Variant; Work; Writing; acquired epilepsy; aged; arthropod-borne; career; career development; clinical examination; design; early detection biomarkers; epidemiology study; exome sequencing; genetic variant; global health; improved; insight; member; neglected tropical diseases; population health; prevent; proband; recruit; responsible research conduct; risk mitigation; segregation; socioeconomics; trait

Project Summary The K01 application for Dr. Rajarshi Mazumder, a board-certified epileptologist at University of California, Los Angeles, will allow him to establish as an independent investigator in global health and epilepsy research. The K01 will provide Dr. Mazumder support and protect time to achieve the following career development goals: 1) gain expertise in molecular epidemiology-- training in design and conduct of research using genetic data and model the effects of genes and their interactions with environmental factors; 2) Advanced statistical training for population health; 3) Lead research in a resource-constrained setting and training in the responsible conduct of research in global health; 4) Grant writing. To accomplish his career goals, Dr. Mazumder has assembled a team of mentors with complimentary expertise in Uganda and the US. More than 80% of people with epilepsy live in low-to middle-income countries, where despite the high incidences, many commonly occurring epilepsies remain understudied and poorly characterized. Nodding syndrome and related epilepsies are such a constellation of epileptic brain disorder that occurs in several sub-Saharan African countries. Although the etiology of this disease is unknown, several studies have found a consistent association with the parasite, Onchocerca volvulus (OV). As the OV parasite is not neuroinvasive, autoimmunity to Hu-Leiomodin-1, a muscle-associated protein, due to molecular mimicry with OV antigens is thought to play a role in the pathogenesis. Studies have also found that variations in immune responses due to HLA polymorphism might also contribute to the etiology. However, the role of host genetics and its relationship to exposure to OV in the manifestation of epilepsy is yet to be systematically investigated. The central hypothesis of this proposal is that families with NS share common electroclinical features forming a distinct familial epilepsy syndrome and this electroclinical phenotype is conferred by O. volvulus-associated hu-Leiomodin-1 autoimmunity in genetically susceptible individuals. We will pursue the following aims: 1) Characterize the epilepsy sub-phenotypes that aggregate within the NS-affected families; 2) Investigate the role of genetic polymorphism in the human host underlying the pathogenesis of NS-and related epilepsies; 3) Evaluate the relationship between exposure to OV-associated Hu-leiomodin-1 antibody and host susceptibility that jointly confers risk for NS-and related epilepsies. This study has a high global health significance, as it aims to mechanistically understand how a parasitic disease modifies the risk of epilepsy in susceptible individuals. There is an urgent need of this evaluation to further mitigate the risk of a neglected tropical disease. The proposal will prepare Dr. Mazumder as an independent researcher and provide the foundation for future R01 funded studies to prevent acquired epilepsies by early identification of susceptible individuals.

项目摘要 K01 Rajarshi Mazumder博士的申请 Angeles将允许他成为全球健康和癫痫研究的独立研究者。这 K01将为Mazumder博士提供支持并保护时间以实现以下职业发展目标：1） 获得分子流行病学方面的专业知识 - 使用遗传数据和研究培训研究和进行研究的培训 建模基因的影响及其与环境因素的相互作用； 2）高级统计培训 人口健康； 3）在资源受限的环境和培训中领导研究负责任的行为 全球健康研究； 4）赠款写作。为了实现他的职业目标，Mazumder博士聚集了 在乌干达和美国拥有免费专业知识的导师团队。超过80％的癫痫患者 生活在低到中等收入国家，尽管发生了很高的事件，但许多通常发生 癫痫病仍在研究且特征不佳。点头综合征和相关癫痫是这样的 撒哈拉以南非洲国家发生癫痫脑疾病的星座。虽然 该疾病的病因尚不清楚，几项研究发现与寄生虫有一致的关联， OnChocerca volvulus（OV）。由于OV寄生虫不是神经性侵染的，因此自身免疫性为hu-leiomodin，a 由于与OV抗原的分子模仿，肌肉相关的蛋白质被认为在 发病。研究还发现，由于HLA多态性引起的免疫反应的变化可能 也有助于病因。但是，宿主遗传学的作用及其与暴露于OV的关系 癫痫的表现尚待系统地研究。该提议的核心假设是 具有NS共享常见电细胞特征的家庭形成了独特的家族性癫痫综合征，这 电细胞表型由O. volvulus相关的Hu-Leiomodin-1自身免疫赋予遗传学 敏感的人。我们将追求以下目的：1）表征癫痫子表型 在受NS影响的家庭中汇总； 2）研究遗传多态性在人宿主中的作用 NS和相关癫痫的发病机理的基础； 3）评估暴露之间的关系 OV相关的Hu-Leiomodin-1抗体和宿主敏感性共同赋予NS和相关风险 癫痫病。这项研究具有很高的全球健康意义，因为它旨在机械地了解 寄生疾病改变了易感人群癫痫的风险。迫切需要这个 评估以进一步减轻被忽视的热带疾病的风险。该提案将为Mazumder博士做好准备 作为独立研究人员，为未来的R01资助研究提供基础，以防止获得 通过早期识别易感人士的癫痫病。