Experimental Cellular Approaches to Genotype × Environment Interaction
基因型与环境相互作用的实验细胞方法
基本信息
- 批准号:10630638
- 负责人:
- 金额:$ 161.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-07 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAgingAir PollutionBehaviorBenzo(a)pyreneBiologicalBiological MarkersBlood CellsBrainCell LineCellsCellular StressComplexCryopreservationDerivation procedureDetectionDimensionsDiseaseEnvironmentEnvironmental ExposureEnvironmental PollutantsEpidemiologyEpigenetic ProcessEtiologyFamily StudyGene Expression ProfileGenerationsGenesGeneticGenetic TranscriptionGenetic studyGenotypeHealthHeritabilityHeterogeneityHomeostasisHumanHuman ResourcesIndividualLengthMeasuresMetabolismMexican AmericansMitochondriaOrganParticipantPathway interactionsPhenotypePollutionResearch DesignRisk FactorsSnake VenomsStressTailTechniquesTestingTimeVariantWhole Organismalveolar epitheliumbiomarker identificationcell typedesignepidemiology studyepigenetic memoryfitnessfrailtygenetic approachgenetic pedigreehuman modelhuman subjectinduced pluripotent stem cellinduced pluripotent stem cell technologyinnovationlymphoblastoid cell linenerve stem cellneurotoxicnovelnovel strategiesphosphoproteomicspleiotropismresponsesingle cell sequencingstress resiliencetelomere
项目摘要
PROJECT SUMMARY
We propose to perform a novel study in the field of cellular epidemiology, that has been made possible by
the recent revolution in induced pluripotent stem cell (iPSC) technology. It is well known that there are many cell-
specific functions and behaviors that have been missed by the limitations of having to rely on easily obtainable
cells, such as blood cells or lymphoblastoid cell lines, for epidemiological studies of disease causation, risk
factors, and biomarker identification. Advances in iPSC technologies now allow us to consider non-invasive
large-scale deep cellular phenotyping efforts on disease-appropriate cell types in human subjects. Robust
derivation of iPSC lines and their differentiation into organ-specific cell types is possible from blood cells. An
important benefit of iPSC-derived cells is that observed biological variation primarily represents genetic
influences, since most of the epigenetic memory of the historical organismal environment is lost.
Our proposed study involves an innovative experimental approach to human genotype×environment
interaction (GEI). While GEI is thought to exist widely, it is relatively poorly studied in humans due to
environmental heterogeneity and the difficulty of controlling environmental exposures. Our iPSC-based cellular
approach allows us to rigorously test for GEI experimentally by examining cellular phenotypic variation before
and after a controlled environmental challenge. Our study will be the first and largest study to model human GEI
in two different iPSC-derived cell types. First, we will determine if the expected neurotoxic effect of snake venom
in neural stem cells (NSCs) is genetically driven, and secondly, whether the suspected differential response of
alveolar epithelial type 2 cells (AT2s) to environmental pollutant exposure has a genetic basis.
This project will leverage a major existing human resource, the Mexican American Family Study (MAFS). We
will use existing cryo-preserved iPSC lines from 400 MAFS participants for the generation of well-characterized
NSCs and AT2. We propose a novel experimental and efficient pedigree-based approach for studying the genetic
basis of cellular response to environmental stress (i.e, GEI), which has previously been difficult to assess. Our
aims are: 1) assess genetic basis of NSC response to snake venom; 2) assess genetic basis of AT2 response
to a benzo[a]pyrene pollution; 3) examine the genetic basis of environmental disruption of cellular transcriptional
coherence/homeostasis; and 4) identify pleiotropic effects of cellular stress resilience on human organismal
phenotypes relevant to health.
This project will employ a novel experimental and efficient pedigree-based approach for studying human GEI,
which has previously been difficult to assess. It also will help establish the feasibility of epidemiological scale
utilization of iPSC technology to attack biomedical problems. Finally, we expect that the proposed project will
rigorously establish the cellular basis of GEI influencing complex phenotypes of relevance to human health.
项目总结
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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{{ truncateString('John Blangero', 18)}}的其他基金
Research Project 2 - Genomic Approaches to Pollutome Effects on Risk of Major Depression in Hispanic Pedigrees
研究项目 2 - 污染组学方法对西班牙裔谱系中重度抑郁症风险的影响
- 批准号:
10749788 - 财政年份:2023
- 资助金额:
$ 161.78万 - 项目类别:
Shared Genetic and Environmental Influences on Age-Related Hearing Loss, Cognitive Decline, and Dementia Risk
遗传和环境对与年龄相关的听力损失、认知能力下降和痴呆风险的共同影响
- 批准号:
10658077 - 财政年份:2023
- 资助金额:
$ 161.78万 - 项目类别:
Identification of the Exposome in Fatty Liver Disease in Mexican American Families Using Genetic Correction
使用基因校正鉴定墨西哥裔美国人家庭脂肪肝中的暴露组
- 批准号:
10057266 - 财政年份:2018
- 资助金额:
$ 161.78万 - 项目类别:
Analysis Core Rio Grande Valley AD-RCMAR
里奥格兰德河谷分析核心 AD-RCMAR
- 批准号:
10241359 - 财政年份:2018
- 资助金额:
$ 161.78万 - 项目类别:
Identification of the Exposome in Fatty Liver Disease in Mexican American Families Using Genetic Correction
使用基因校正鉴定墨西哥裔美国人家庭脂肪肝中的暴露组
- 批准号:
10307087 - 财政年份:2018
- 资助金额:
$ 161.78万 - 项目类别:
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