Toxicodietary and genetic determinants of susceptibility to neurodegeneration

描述（由申请人提供）：我们提出一项美国/刚果民主共和国合作项目，以阐明食物（木薯，Manihot esculenta Crantz）氰毒素与撒哈拉以南非洲运动系统疾病（称为konzo）发生之间的关系。konzo的病因在很大程度上仍不清楚，儿童期和成年期可能存在其他形式的与木薯相关的神经发育/认知障碍。我们将汇集具体国家的研究能力和需求，以实现以下目标：(a)阐明木薯神经毒性对人类运动和认知能力的影响，(b)增加对环境压力源（毒物）、饮食（营养状况）和与运动系统退化有关的遗传之间寿命相互作用的理解，(c)并增强刚果民主共和国（DRC）的临床/神经毒理学研究能力。我们的中心假设是，木薯相关运动/认知缺陷（MCD）的风险是由慢性硫氨基酸缺乏和/或遗传变异决定的，这些变异会损害木薯氰素的代谢，随后会增加氰酸盐（神经毒素）的产生和神经变性的风险。为了验证我们的假设并实现我们的目标，我们将解决以下具体目标：(1)阐明与长期饮食依赖木薯相关的运动认知缺陷（MCD）的流行病学模式，(2)确定MCD与硫氨基酸缺乏和氰解毒酶罗丹斯（硫代硫酸盐硫转移酶）遗传多态性相关的风险，以及(3)增加刚果民主共和国临床/神经毒理学研究的人力。MCD将通过横断面研究（基线表征）中的神经心理学测试来确定，然后采用病例队列设计来捕获学龄儿童的神经发育迟缓。TST多态性将使用基于pcr的测序技术进行研究。血清氨基甲酰化将使用最先进的蛋白质组学方法进行分析和定量，即液相色谱串联质谱（LC/MS-MS）。年轻的刚果民主共和国调查人员将通过积极参与有监督的实地工作和职业发展指导来接受培训。的相关性。在完成拟议的研究后，我们的研究结果将有助于制定科学依据，以解决和制定减少与木薯相关的神经毒性负担的策略，木薯是全球超过5亿人的主食。该提案的总体目标与NIH的全球健康使命相吻合，同时整合了FIC、NIEHS、NINDS和NICHD的研究所特定使命。

DESCRIPTION (provided by applicant): We propose a USA/DRC collaborative project to elucidate the relationship between food (cassava, Manihot esculenta Crantz) cyanogenic toxins and the occurrence of a motor system disease --- known as konzo --- in sub-Saharan Africa. The causes of konzo have largely remained unclear, and other forms of cassava-related neurodevelopmental/cognitive impairment may exist during childhood and adult life. We will bring together country-specific research capabilities and needs to reach the following goals: (a) illuminate the impact of cassava neurotoxicity on human motor and cognition abilities, (b) increase understanding of lifespan interactions between environmental stressors (toxicants), diet (nutritional status), and genetics in relation to motor system degeneration, (c) and enhance the clinical/neurotoxicolgy research capacity of the Democratic Republic of Congo (DRC). Our central hypothesis is that risk for cassava-associated motor/cognition deficits (MCD) is determined by chronic sulfur amino acid-deficiency and/or genetic variations that impair the metabolism of cassava cyanogens with subsequent increase in cyanate (neurotoxin) production and risk for neurodegeneration. To test our hypothesis and achieve our goals, we will address the following specific aims: (1) elucidate the epidemiological pattern of motor cognition deficits (MCD) associated with chronic dietary reliance on cassava, (2) determine the risk for MCD in relation to sulfur amino acid deficiency and genetic polymorphisms in the cyanogen-detoxifying enzyme rhodanese (thiosulfate sulfurtransferase), and (3) increase the manpower for clinical/neurotoxicology research in DRC. MCD will be ascertained by neuropsychological testing in a cross-sectional study (baseline characterization) followed by a case-cohort design to capture neurodevelopmental delays in school-age children. TST polymorphisms will be studied using PCR-based sequencing techniques. Serum carbamoylation will be analyzed and quantified using state-of-the-art proteomic methodologies i.e. liquid chromatography tandem mass spectrometry (LC/MS-MS). Young DRC investigators will be trained through active participation in supervised field work and mentoring for career development. Relevance. At the completion of the proposed studies, our findings will help develop a scientific rationale to address and develop strategies to reduce the burden of neurotoxicity associated with cassava, a staple food for more than 500 million people around the globe. The overall goal of this proposal meshes well with the global health mission of the NIH while integrating the institute-specific missions of FIC, NIEHS, NINDS, and NICHD.