Toxicodietary and genetic determinants of susceptibility to neurodegeneration

描述（由申请人提供）：我们提出了一个美国/刚果民主共和国的合作项目，以阐明食物（木薯，木薯）生氰毒素和运动系统疾病的发生之间的关系-被称为konzo -在撒哈拉以南非洲。konzo的原因在很大程度上仍然不清楚，其他形式的木薯相关的神经发育/认知障碍可能存在于儿童和成年生活中。我们将汇集各国的研究能力和需求，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）增加对环境压力之间的寿命相互作用的理解（毒物），饮食（营养状况）和与运动系统退化有关的遗传学，（c）加强刚果民主共和国的临床/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）的风险由慢性含硫氨基酸缺乏和/或遗传变异决定，这些变异损害木薯氰的代谢，随后增加氰酸盐（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）阐明与长期依赖木薯饮食相关的运动认知缺陷（MCD）的流行病学模式，（2）确定MCD与含硫氨基酸缺乏和氰解毒酶Rhodanese基因多态性相关的风险（硫代硫酸盐硫转移酶），（3）增加刚果民主共和国临床/神经毒理学研究的人力。将在横断面研究（基线表征）中通过神经心理学测试确定MCD，随后采用病例队列设计，以捕获学龄儿童的神经发育迟缓。将使用基于PCR的测序技术研究TST多态性。将使用最先进的蛋白质组学方法（即液相色谱串联质谱法（LC/MS-MS））分析和定量血清氨甲酰化。将通过积极参与监督下的实地工作和职业发展辅导，对刚果民主共和国的年轻调查员进行培训。本案无关在拟议的研究完成后，我们的研究结果将有助于制定科学的理由，以解决和制定战略，以减少与木薯有关的神经毒性负担，木薯是地球仪各地5亿多人的主食。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的机构特定使命。

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.