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 Rajarshi Mazumder博士的K 01申请，他是加州大学洛杉矶分校的一名委员会认证的癫痫病学家。 洛杉矶，将使他成为全球健康和癫痫研究的独立调查员。的 K 01将为Mazumder博士提供支持和保护时间，以实现以下职业发展目标：1） 获得分子流行病学方面的专门知识-利用遗传数据设计和开展研究方面的培训， 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， 3）在资源有限的环境中领导研究，并在负责任的行为方面进行培训 全球健康研究; 4）撰写资助论文。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丰富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，但许多常见的 癫痫仍然没有得到充分的研究和很好的表征。点头综合征和相关的癫痫是这样一个 在撒哈拉以南的非洲国家，癫痫性脑功能紊乱是一种常见的疾病。虽然 这种疾病的病因是未知的，几项研究发现了与寄生虫的一致关联， 盘尾丝虫（OV）。由于OV寄生虫不是神经侵入性的，因此对Hu-Leiomodin-1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HLA多态性引起的免疫反应的变化可能与人类免疫缺陷有关。 也有助于病因学。然而，宿主遗传学的作用及其与暴露于OV的关系， 癫痫的临床表现尚待系统研究。这一提议的核心假设是， NS家族有共同的电临床特征，形成独特的家族性癫痫综合征， 电临床表型由O.肠扭转相关的hu-Leiomodin-1自身免疫在遗传学上 易受影响的个体。我们将追求以下目标：1）表征癫痫亚表型， 2）研究遗传多态性在人类宿主中的作用 NS及相关癫痫发病机制的基础; 3）评估暴露于 Ov-associated Hu-leiomodin-1抗体和宿主易感性共同赋予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，因为它旨在从机制上了解 寄生虫病改变了易感个体患癫痫的风险。我们迫切需要这样做 评估，以进一步减轻被忽视的热带疾病的风险。这个提案会让马祖姆德博士 作为一个独立的研究人员，并为未来的R 01资助的研究，以防止获得性 通过早期识别易感个体来预防癫痫。