Choline Polymorphisms in FASD

FASD 中的胆碱多态性

• 批准号: 10331893
• 负责人: SUSAN M. SMITH
• 金额: $ 17.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331893
• 关键词: 3' Untranslated Regions; Address; Affect; Age; Alleles; Behavioral; Biochemical; Brain; Carbon; Cell Line; Cell membrane; Child; Choline; Clinical Research; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Databases; Development; Diagnosis; Dose; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Infant; Intake; Intervention; Intervention Trial; Investigation; Life; Link; Memory; Metabolism; Minor; Modeling; Neurons; Nutrient; Outcome; Phase; Pilot Projects; Positioning Attribute; Pregnancy; Prevention; Protein Isoforms; Proteins; Reporting; Research Personnel; Role; Shapes; Single Nucleotide Polymorphism; Source; Substance abuse problem; Supplementation; Testing; Toddler; Variant; Woman; Work; behavior influence; behavioral outcome; choline supplementation; choline transporter; cognitive benefits; cognitive disability; cognitive performance; cohort; dietary; disability; experience; genetic variant; improved; improved outcome; in utero; molecular sequence database; neurobehavior; neurobehavioral; novel; nutrition; personalized medicine; postnatal; pre-clinical; prenatal; response; success; whole genome; 3' Untranslated Regions; Address; Affect; Age; Alleles; Behavioral; Biochemical; Brain; Carbon; Cell Line; Cell membrane; Child; Choline; Clinical Research; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Databases; Development; Diagnosis; Dose; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Infant; Intake; Intervention; Intervention Trial; Investigation; Life; Link; Memory; Metabolism; Minor; Modeling; Neurons; Nutrient; Outcome; Phase; Pilot Projects; Positioning Attribute; Pregnancy; Prevention; Protein Isoforms; Proteins; Reporting; Research Personnel; Role; Shapes; Single Nucleotide Polymorphism; Source; Substance abuse problem; Supplementation; Testing; Toddler; Variant; Woman; Work; behavior influence; behavioral outcome; choline supplementation; choline transporter; cognitive benefits; cognitive disability; cognitive performance; cohort; dietary; disability; experience; genetic variant; improved; improved outcome; in utero; molecular sequence database; neurobehavior; neurobehavioral; novel; nutrition; personalized medicine; postnatal; pre-clinical; prenatal; response; success; whole genome

ABSTRACT This exploratory/developmental UH2 pilot application to CIFASD addresses the need for improved intervention in Fetal Alcohol Spectrum Disorder (FASD), a leading cause of life-long behavioral and cognitive disability. This proposal focuses on the nutrient choline, a one-carbon donor that is essential for healthy brain development. Polymorphisms in choline-metabolizing genes affect its synthesis, transport, and utilization, and thus affect choline need and efficacy of its use. Strong preclinical data show that choline supplementation – both in utero and postnatally – mitigates the cognitive deficits due to prenatal alcohol exposure (PAE). Clinical studies have more nuanced outcomes, and choline supplements confer more modest or even no benefit; however, variables including age, developmental brain stage, and duration confound the interpretation. Our recent SNP analysis of subjects in the Wozniak intervention found that polymorphisms in the choline transporter SLC44A1 (CTL1) predict who benefited most from choline; specifically, subjects having minor alleles in SLC44A1 have the greatest memory improvement when given supplemental choline. SLC44A1 is ubiquitous and its activity is reduced by low choline intake, and these minor alleles further reduce its activity. Thus, those with the minor alleles are the most vulnerable to choline inadequacy and benefit most from its supplementation. Here, we collaborate with CIFASD investigators to investigate the role of SLC44A1 in FASD. Specifically, we hypothesize that polymorphisms in SLC44A1 significantly influence behavioral outcomes in FASD, in both the presence and absence of choline intervention. Aim 1 tests the hypothesis that, within the Ukrainian intervention trial, those PAE pregnancies with minor alleles in SLC44A1 derive the greatest cognitive benefit from choline supplementation. Aim 2 tests the hypothesis that, of individuals diagnosed with FASD and not receiving choline, those having minor alleles in SLC44A1 will have the poorest cognitive performance. Aim 3 expresses these minor allelic proteins in a human neuronal lineage, to understand the functional consequence of these variants to choline transport and metabolism. Aims 1-2 utilize the CIFASD database, in a collaboration with CIFASD investigators Christina Chambers, Tatiana Foroud and Jeffrey Wozniak, and with choline expert Steven Zeisel. These findings (i) identify who benefits most from choline intervention; (ii) informs how choline improves outcomes in FASD; and (iii) enables optimization of the choline intervention. This study represents the first application of Personalized Medicine to FASD. The results position us to join a CIFASD U01 that would validate SLC44A1's influence in an independent cohort of gestational substance abuse, with testing for additional choline-related polymorphisms that further influence response to choline intervention.

抽象的 CIFASD的探索性/发展性UH2试点申请解决了改进干预的需求 在胎儿酒精谱系障碍（FASD）中，这是终身行为和认知障碍的主要原因。 该提议重点是营养胆碱，这是一种对健康大脑必不可少的单碳供体 发展。胆碱代谢基因中的多态性会影响其合成，运输和利用，并且 因此会影响胆碱的需求和使用的有效性。强有力的临床前数据表明，补充胆碱 - 在子宫内和产后 - 减轻由于产前酒精暴露（PAE）引起的认知缺陷。临床 研究的成果更加细微，胆碱补充会议会更适度甚至没有好处。 但是，变量包括年龄，发育性大脑阶段和持续时间混淆解释。我们的 Wozniak干预中受试者的最新SNP分析发现胆碱中的多态性 转运蛋白SLC44A1（CTL1）预测​​谁从胆碱中受益最多；具体而言，受试者有次要 当给予补充胆碱时，SLC44A1中的等位基因的记忆力最大。 Slc44a1是 无处不在的胆碱摄入量降低了无处不在的活性，这些小等位基因进一步降低了其活性。 那就是那些带有次要等位基因的人最容易受到胆碱不足的影响，并且从中受益最大 补充。在这里，我们与CIFASD研究人员合作研究了SLC44A1在FASD中的作用。 特别是，我们假设SLC44A1中的多态性显着影响 FASD，在存在和不存在胆碱干预的情况下。 AIM 1检验了以下假设 乌克兰干预试验，SLC44A1中有未成年等位基因的PAE怀孕是最大的认知 补充胆碱的好处。 AIM 2检验了以下假设，即被诊断为FASD和 在SLC44A1中没有少数等位基因的人没有接受胆碱的认知表现最差。目的 3在人神经元谱系中表达这些次要等位基因蛋白，以了解功能 这些变体对胆碱运输和代谢的结果。 AIMS 1-2利用CIFASD数据库 与CIFASD调查人员Christina Chambers，Tatiana Foroud和Jeffrey Wozniak的合作，以及与 胆碱专家史蒂文·蔡司（Steven Zeisel）。这些发现（i）确定谁从胆碱干预中受益最大； （ii）告知 胆碱如何改善FASD的结果； （iii）可以优化胆碱干预。这项研究 代表了个性化药物在FASD中的首次应用。结果使我们加入CIFASD U01将验证SLC44A1在独立的妊娠药物滥用队列中的影响，与 测试其他与胆碱相关的多态性，这些多态性进一步影响对胆碱干预的反应。