Toxicodietary and genetic determinants of susceptibility to neurodegeneration

神经退行性疾病易感性的毒性饮食和遗传决定因素

• 批准号: 9145383
• 负责人: Daniel Desire Tshala-Katumbay
• 金额: $ 2.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145383
• 关键词: Address; Adult; Affect; Africa South of the Sahara; Albumins; Ankle; Base Sequence; Biochemical; Brazilian Arrowroot; Chemicals; Child; Childhood; Chronic; Clinical; Clonus; Cognition; Consumption; Country; Cross-Sectional Studies; Cyanides; Democratic Republic of the Congo; Dependency; Development; Diet; Dietary intake; Disease; Disease Outbreaks; Drug Metabolic Detoxication; Enzymes; Epidemiology; Family; Family history of; Food; Funding; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Goals; Gold; Heritability; Human; Human Resources; Impaired cognition; Individual; Industry; Institutes; Institution; International; Investigation; Life; Liquid Chromatography; Longevity; Malnutrition; Manihot; Mediating; Mental Retardation; Mentors; Metabolism; Methodology; Methods; Mining; Mission; Modification; Motor; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; National Institute of Neurological Disorders and Stroke; Nature; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neuronal Dysfunction; Neuropsychological Tests; Neurotoxins; Nutritional status; Occupational; Paralysed; Pathogenesis; Pathway interactions; Pattern; Phenotype; Population; Predisposition; Prevalence; Process; Production; Proteins; Proteomics; Rattus; Reflex action; Research; Research Activity; Research Personnel; Risk; Risk Factors; Safety; School-Age Population; Security; Serum; Serum Albumin; Spastic Paraparesis; Specific qualifier value; Spinal Cord; Sulfur Amino Acids; Supervision; System; Techniques; Testing; Thiocyanates; Thiosulfate Sulfurtransferase; Time; Toxicology; Toxin; Training; United States National Institutes of Health; Upper Motor Neuron Disease; Variant; War; Woman; Work; Yucca; bean; career development; case control; cohort; cyanogen; design; diabetes risk; environmental stressor; genetic pedigree; global health; liquid chromatography mass spectrometry; motor disorder; neuropsychological; neurotoxicity; neurotoxicology; optic nerve disorder; prevent; somatosensory; tandem mass spectrometry; toxicant; translational approach

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.

描述（由申请人提供）：我们提出了一个美国/刚果民主共和国合作项目，旨在阐明食物（木薯、木薯）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，在儿童期和成年期可能存在其他形式的木薯相关神经发育/认知障碍。我们将汇集各国具体的研究能力和需求，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) 增进对环境压力因素（有毒物质）、饮食（营养状况）和与运动系统退化相关的遗传学之间的生命周期相互作用的了解，(c) 并增强民主共和国的临床/神经毒理学研究能力 刚果（金）。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。为了检验我们的假设并实现我们的目标，我们将实现以下具体目标：（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）确定与硫氨基酸缺乏和氰解毒酶硫代硫酸盐（硫代硫酸盐）基因多态性相关的 MCD 风险 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。 MCD 将通过横断面研究（基线特征）中的神经心理学测试来确定，然后进行病例队列设计，以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。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) 对血清氨甲酰化进行分析和定量。刚果民主共和国的年轻调查员将通过积极参与受监督的实地工作和职业发展指导来接受培训。关联。在拟议的研究完成后，我们的研究结果将有助于制定科学依据来解决和制定减轻木薯相关神经毒性负担的策略，木薯是全球 5 亿多人的主食。该提案的总体目标与 NIH 的全球卫生使命完美契合，同时整合了 FIC、NIEHS、NINDS 和 NICHD 的机构特定使命。