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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：
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
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：
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

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