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

基本信息

批准号：
8429486
负责人：
Daniel Desire Tshala-Katumbay
金额：
$ 30.92万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429486
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 Functional disorder Funding Genetic Genetic Determinism Genetic Polymorphism Genetic Variation Goals Gold Heritability Human Human Resources Impaired cognition Impairment Individual Industry Institutes Institution International Investigation Life Liquid Chromatography Longevity Malnutrition Manihot Manihot esculenta 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 Neuronal Dysfunction Neuropsychological Tests Neurotoxins Nutritional status Occupational Paralysed Pathogenesis Pathway interactions Pattern Phenotype Population Predisposition Prevalence Process Production Proteins Proteomics Rattus Reflex action Reliance 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 neuropsychological neurotoxicity neurotoxicology optic nerve disorder prevent somatosensory tandem mass spectrometry toxicant translational approach

项目摘要

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/DRC协作项目，以阐明食品（木薯，Manihot esculenta crantz）氰基毒素与运动系统疾病的发生之间的关系 - 在撒哈拉以外的非洲地区konzo-konzo-闻名。 konzo的原因在很大程度上尚不清楚，其他形式的木薯相关神经发育/认知障碍可能会在儿童期和成人生活中存在。我们将汇集国家特定的研究能力，并需要达到以下目标：（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（毒性）之间寿命相互作用的理解，饮食（毒性），饮食（养分）和遗传学对运动的临床和遗传学的影响（C），以及遗传学的临床（C）（C）（C）（C）（C）（C）（C）刚果（DRC）。我们的核心假设是，木薯相关的运动/认知缺陷（MCD）的风险取决于慢性硫氨基酸缺乏和/或遗传变异，这些变异会损害木薯cyanogens的代谢，而随后的氰酸酯（神经毒素）生产和神经化学风险的随后增加。 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硫转移酶）和（3）增加刚果民主共和国临床/神经毒理学研究的人力。在横断面研究（基线表征）中，将通过神经心理学测试来确定MCD，然后是案例 - 霍特设计，以捕获学龄儿童中的神经发育延迟。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）分析和量化血清卡马酰胺化。年轻的刚果民主共和国调查人员将通过积极参与监督现场工作和指导职业发展培训。关联。拟议的研究完成后，我们的发现将有助于制定科学原理，以解决和制定策略来减轻与木薯相关的神经毒性负担，这是全球超过5亿人的主食。该提案的总体目标与NIH的全球健康使命融为一体，同时将FIC，NIEHS，NINDS和NICHD的研究所特定的任务整合在一起。