Choline Polymorphisms in FASD
FASD 中的胆碱多态性
基本信息
- 批准号:10331893
- 负责人:
- 金额:$ 17.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3&apos Untranslated RegionsAddressAffectAgeAllelesBehavioralBiochemicalBrainCarbonCell LineCell membraneChildCholineClinical ResearchClinical TrialsCodeCognitionCognitiveCognitive deficitsCollaborationsDataDatabasesDevelopmentDiagnosisDoseFetal Alcohol ExposureFetal Alcohol Spectrum DisorderFutureGTP-Binding Protein alpha Subunits, GsGenesGeneticGenetic PolymorphismGenotypeHumanIndividualInfantIntakeInterventionIntervention TrialInvestigationLifeLinkMemoryMetabolismMinorModelingNeuronsNutrientOutcomePhasePilot ProjectsPositioning AttributePregnancyPreventionProtein IsoformsProteinsReportingResearch PersonnelRoleShapesSingle Nucleotide PolymorphismSourceSubstance abuse problemSupplementationTestingToddlerVariantWomanWorkbehavior influencebehavioral outcomecholine supplementationcholine transportercognitive benefitscognitive disabilitycognitive performancecohortdietarydisabilityexperiencegenetic variantimprovedimproved outcomein uteromolecular sequence databaseneurobehaviorneurobehavioralnovelnutritionpersonalized medicinepostnatalpre-clinicalprenatalresponsesuccesswhole genome
项目摘要
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.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SUSAN M. SMITH其他文献
SUSAN M. SMITH的其他文献
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{{ truncateString('SUSAN M. SMITH', 18)}}的其他基金
Craniofacial Morphogenesis in Prenatal Alcohol Exposure
产前酒精暴露中的颅面形态发生
- 批准号:
10025955 - 财政年份:2019
- 资助金额:
$ 17.49万 - 项目类别:
Prenatal alcohol exposure disrupts maternal-fetal iron metabolism in FASD
产前酒精暴露会扰乱 FASD 母胎铁代谢
- 批准号:
8677237 - 财政年份:2014
- 资助金额:
$ 17.49万 - 项目类别:
Prenatal alcohol exposure disrupts maternal-fetal iron metabolism in FASD
产前酒精暴露会扰乱 FASD 母胎铁代谢
- 批准号:
8857181 - 财政年份:2014
- 资助金额:
$ 17.49万 - 项目类别:
Craniofacial Morphogenesis in Prenatal Alcohol Exposure
产前酒精暴露中的颅面形态发生
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8134114 - 财政年份:2010
- 资助金额:
$ 17.49万 - 项目类别:
Is Maternal Iron Status a Risk Factor in Fetal Alcohol Syndrome?
母亲的铁状况是胎儿酒精综合症的危险因素吗?
- 批准号:
7804567 - 财政年份:2009
- 资助金额:
$ 17.49万 - 项目类别:
14th Biennial FASEB Summer Research Conference on Retinoids
第 14 届 FASEB 类视黄醇双年度夏季研究会议
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7479974 - 财政年份:2008
- 资助金额:
$ 17.49万 - 项目类别:
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