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

项目摘要 加州大学洛杉矶分校董事会认证的癫痫专家Rajarshi Mazumder博士的K01申请 在洛杉矶，他将成为全球健康和癫痫研究的独立调查员。这个 K01将为Mazumder博士提供支持，并为实现以下职业发展目标保护时间：1) 获得分子流行病学方面的专业知识--利用遗传数据设计和进行研究的培训 对基因的影响及其与环境因素的相互作用进行建模；2)高级统计培训 人口健康；3)在资源有限的情况下领导研究，并就负责任的行为进行培训 全球健康研究；4)赠款写作。为了实现他的职业目标，Mazumder博士组建了一个 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 生活在低收入到中等收入国家，尽管发病率很高，但许多情况经常发生 癫痫的研究仍然很少，特征也很差。点头综合症和相关的癫痫就是这样一种 在撒哈拉沙漠以南的几个非洲国家出现的癫痫脑紊乱的星座。尽管 这种疾病的病因尚不清楚，几项研究发现与这种寄生虫有一致的联系， 螺旋体丝虫(OV)。由于卵子寄生虫不是神经侵袭性的，因此对Hu-leiomodin-1，a的自身免疫。 肌肉相关蛋白，由于与OV抗原的分子模拟，被认为在 发病机制。研究还发现，由于人类白细胞抗原多态而引起的免疫反应的变化可能 也与病因学有关。然而，宿主遗传学的作用及其与卵子感染的关系 癫痫的表现尚待系统研究。这项提议的中心假设是 患有NS的家族有共同的电临床特征，形成了独特的家族性癫痫综合征，这 电临床表型是由旋毛虫相关的人Leiomodin-1自身免疫在遗传上赋予的 易感人群。我们将追求以下目标：1)表征癫痫的亚型， 在受NS影响的家系内聚集；2)调查遗传多态在人类宿主中的作用 NS-和相关癫痫的发病机制；3)评估暴露于 OV相关的Hu-Leiomodin-1抗体和宿主易感性共同增加NS及相关疾病的风险 癫痫。这项研究具有很高的全球健康意义，因为它旨在机械地理解 寄生虫病改变了易感人群患癫痫的风险。这是一种迫切的需要 进一步减轻一种被忽视的热带疾病风险的评估。该提案将使Mazumder博士准备好 作为独立研究人员，并为未来R01资助的研究提供基础，以防止获得性 通过早期识别易感个体来治疗癫痫。

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.