Toxicodietary and genetic determinants of susceptibility to neurodegeneration

描述(由申请者提供)：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、甘露糖)氰化物毒素与撒哈拉以南非洲一种运动系统疾病-Konzo--的发生之间的关系。魔芋的病因在很大程度上仍不清楚，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人生活中。我们将汇集各国的研究能力，并需要实现以下目标：(A)阐明木薯神经毒性对人类运动和认知能力的影响，(B)提高对环境应激源(毒物)、饮食(营养状况)和与运动系统退化有关的遗传学之间的寿命相互作用的了解，(C)并加强刚果民主共和国(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，木薯相关的运动/认知缺陷(MCD)的风险是由慢性含硫氨基酸缺乏和/或基因变异决定的，这些变异损害了木薯氰化物的新陈代谢，从而增加了氰酸盐(神经毒素)的产生和神经退化的风险。为了验证我们的假设并实现我们的目标，我们将致力于以下具体目标：(1)阐明与长期饮食依赖木薯有关的运动认知缺陷(MCD)的流行病学模式，(2)确定与硫磺氨基酸缺乏和氰基解毒酶硫代硫酸酯(硫代硫酸盐硫代转移酶)基因多态性有关的MCD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将通过一项横断面研究中的神经心理测试(基线特征)来确定，然后进行病例队列设计，以捕捉学龄儿童的神经发育迟缓。将使用基于聚合酶链式反应的测序技术来研究TST多态。血清氨甲酰化将使用最先进的蛋白质组学方法，即LC/MS-MS(LC/MS-MS)进行分析和定量。将通过积极参与受监督的实地工作和指导职业发展来培训年轻的刚果民主共和国调查人员。关联性。在拟议的研究完成后，我们的发现将有助于建立科学的理论基础，以解决和开发战略，以减轻与木薯相关的神经毒性负担，木薯是全球超过5亿人的主食。这项提案的总体目标与NIH的全球卫生使命很好地结合在一起，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.