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SPP1, Oxidative Stress, and Lead Toxicity

SPP1、氧化应激和铅毒性

基本信息

批准号：
10013213
负责人：
Quan Lu
金额：
$ 55万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013213
关键词：
Acetates Adult Animals Antibodies Attenuated Behavior Brain CD44 gene CXCR4 gene Cell Surface Receptors Cell physiology Cells Child Child Health Cities Clustered Regularly Interspaced Short Palindromic Repeats Data Development Discrimination Electroencephalography Environment Environmental Epidemiology Enzymes Epidemiology Failure Functional disorder Gene Expression Gene Targeting Genes Genotype Human Human Genetics Impaired cognition Impairment Injury Integrins Knockout Mice Lead Poisoning Lead levels Link Maps Marble Mediating Modeling Molecular Mus Neuraxis Neurocognitive Neurologic Neurons Odors Oxidative Stress Pathway interactions Phenotype Play Population Predisposition Pregnancy Preventive Intervention Proliferating Promoter Regions Proteins Public Health Recombinants Research Role Shapes Signal Transduction Sleep Small Interfering RNA Social Dominance Stains Testing Therapeutic Therapeutic Intervention Toxic Environmental Substances Up-Regulation Variant Weaning base biological adaptation to stress cell growth cognitive development cohort drinking water field study genetic epidemiology genetic variant genome wide association study improved in vivo indexing knock-down lead contamination lead exposure loss of function mental development mouse model nerve stem cell nestin protein neurobehavioral neurodevelopment neurodevelopmental effect novel offspring osteopontin postnatal period precise genome editing precursor cell prenatal progenitor protective effect reconstitution response restoration self-renewal social stem cells stress reduction transcription factor transcriptome

项目摘要

PROJECT SUMMARY SPP1, Oxidative Stress, and Lead Toxicity Exposure to lead (Pb), a pervasive environmental toxicant, at the early stages of brain development has long-lasting effects on neurocognitive function. However, the molecular mechanisms underlying the unique susceptibility of early brain development to Pb remain poorly understood. As the progenitor cells in the central nervous system, neural stem cells (NSCs) play an essential role in shaping the developing brain. We performed global transcriptional profiling and identified genes whose expression is significantly altered by Pb treatment in neural stem cells. Most of the Pb-upregulated genes are targets of NRF2—the master transcriptional factor for the oxidative stress response, including SPP1 (secreted phosphoprotein 1). SPP1 is known to be neuroprotective, and consistent with this, we demonstrated that addition of recombinant SPP1 protein reduces the inhibitory effect of Pb on NSC growth. Using data from existing genome-wide association studies of an environmental epidemiological cohort, we further showed that a genetic variant in the promoter region of SPP1 significantly associates with improved cognitive development in children. Based on these studies, we hypothesize that NRF2-mediated SPP1 upregulation functions as a self-protective response to reduce Pb exposure-induced injury in neural stem cells. We further hypothesize that failure or compromised ability to upregulate SPP1 in response to Pb exposure contributes to neural stem cell dysfunction and consequently the impairment of early brain development. To test these hypotheses, we propose a highly integrative project that combines molecular mechanistic studies in cultured neural stem cells, in vivo mouse models, and human genetic epidemiology in children exposed to Pb. Aim 1 will investigate the mechanisms thorough which SPP1 upregulation protects against Pb toxicity in neural stem cells. Aim 2 will investigate the role of SPP1 in mediating the effect of Pb on neurodevelopment in mice. Aim 3 will determine the functional association of SPP1 variants with neurodevelopment in children exposed to Pb. Results from this study will establish SPP1 upregulation as a critical mechanism linking Pb exposure with neural stem cell function and neurodevelopment in children, and may identify SPP1 as a novel target for preventative and therapeutic interventions against detrimental neurodevelopment effects of Pb exposure in children.

项目总结