Experimental Cellular Approaches to Genotype × Environment Interaction

基因型与环境相互作用的实验细胞方法

• 批准号: 10630638
• 负责人: John Blangero
• 金额: $ 161.78万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10630638
• 关键词: Age; Aging; Air Pollution; Behavior; Benzo(a)pyrene; Biological; Biological Markers; Blood Cells; Brain; Cell Line; Cells; Cellular Stress; Complex; Cryopreservation; Derivation procedure; Detection; Dimensions; Disease; Environment; Environmental Exposure; Environmental Pollutants; Epidemiology; Epigenetic Process; Etiology; Family Study; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genetic study; Genotype; Health; Heritability; Heterogeneity; Homeostasis; Human; Human Resources; Individual; Length; Measures; Metabolism; Mexican Americans; Mitochondria; Organ; Participant; Pathway interactions; Phenotype; Pollution; Research Design; Risk Factors; Snake Venoms; Stress; Tail; Techniques; Testing; Time; Variant; Whole Organism; alveolar epithelium; biomarker identification; cell type; design; epidemiology study; epigenetic memory; fitness; frailty; genetic approach; genetic pedigree; human model; human subject; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; lymphoblastoid cell line; nerve stem cell; neurotoxic; novel; novel strategies; phosphoproteomics; pleiotropism; response; single cell sequencing; stress resilience; telomere

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.

项目概要 我们提议在细胞流行病学领域进行一项新颖的研究，该研究是通过 最近诱导多能干细胞 (iPSC) 技术的革命。众所周知，有许多细胞 由于必须依赖容易获得的限制而错过的特定功能和行为 细胞，例如血细胞或淋巴母细胞系，用于疾病因果关系、风险的流行病学研究 因素和生物标志物鉴定。 iPSC 技术的进步现在使我们能够考虑非侵入性 对人类受试者中疾病相关细胞类型进行大规模深度细胞表型分析工作。强壮的 iPSC 系的衍生及其分化为器官特异性细胞类型的可能性可以从血细胞中获得。一个 iPSC 衍生细胞的重要好处是观察到的生物变异主要代表遗传 影响，因为历史有机环境的大部分表观遗传记忆都丢失了。 我们提出的研究涉及人类基因型×环境的创新实验方法 互动（GEI）。虽然 GEI 被认为广泛存在，但由于以下原因，它在人类中的研究相对较少 环境异质性和控制环境暴露的难度。我们基于 iPSC 的细胞 该方法使我们能够通过实验之前检查细胞表型变异来严格测试 GEI 以及在受控环境挑战之后。我们的研究将是第一个也是最大的人类 GEI 模型研究 在两种不同的 iPSC 衍生细胞类型中。首先，我们将确定蛇毒是否具有预期的神经毒性作用 神经干细胞（NSC）中的差异是由基因驱动的，其次，是否可疑的差异反应 肺泡上皮2型细胞（AT2s）对环境污染物的暴露具有遗传基础。 该项目将利用现有的主要人力资源——墨西哥裔美国人家庭研究（MAFS）。我们 将使用来自 400 名 MAFS 参与者的现有冷冻保存 iPSC 细胞系来生成特征良好的 iPSC 细胞系 NSC 和 AT2。我们提出了一种新颖的实验性且有效的基于谱系的方法来研究遗传 细胞对环境压力的反应（即GEI）的基础，这在以前很难评估。我们的 目标是：1）评估 NSC 对蛇毒反应的遗传基础； 2) 评估 AT2 反应的遗传基础 苯并[a]芘污染； 3）检查细胞转录环境破坏的遗传基础 一致性/稳态； 4) 确定细胞应激恢复能力对人体有机体的多效性影响 与健康相关的表型。 该项目将采用一种新颖的实验性且高效的基于谱系的方法来研究人类 GEI， 这在以前是很难评估的。它还将有助于建立流行病学规模的可行性 利用 iPSC 技术解决生物医学问题。最后，我们希望拟议的项目能够 严格建立 GEI 影响与人类健康相关的复杂表型的细胞基础。