Signaling Pathway in Ah Receptor-Dependent Control of Hematopoietic Stem Cells

Ah 受体依赖性造血干细胞控制的信号通路

基本信息

批准号：
8556514
负责人：
Thomas A Gasiewicz
金额：
$ 33.98万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8556514
关键词：
Address Age Aging Aging-Related Process Alleles Animal Model Aryl Hydrocarbon Receptor Biology Blood Bone Marrow Transplantation Cell Aging Cell Cycle Cell physiology Cellular biology Chemicals Clinical DNA Damage Data Development Disease Epigenetic Process Equilibrium Etiology Event Exposure to Failure Family Generations Genetic Health Hematologic Neoplasms Hematopoietic Hematopoietic System Hematopoietic stem cells Human Hypoxia Immune system Incidence Laboratories Lead Literature Malignant Neoplasms Mediating Molecular Biology Mus Organism Pancytopenia Pathway interactions Phenotype Physiological Play Premature aging syndrome Process Reactive Oxygen Species Receptor Signaling Regulation Role Signal Pathway Signal Transduction Stress Techniques Testing Therapeutic Tissues Toxic effect Work Xenobiotics base cancer therapy leukemia leukemogenesis member novel oxidative DNA damage oxidative damage pathogen premature public health relevance receptor receptor expression receptor function regenerative response self-renewal senescence stem cell biology stem cell population stressor therapy development tissue regeneration transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood lineages. A balance among quiescence, self-renewal, proliferation, and differentiation is precisely maintained to preserve multi-lineage generation throughout the organism's lifetime, and during responses to stress, tissue damage, and pathogens. Although the dysregulation of these processes in HSCs has immense implications for human health, how this balance is regulated is not well understood. Recent data support the novel hypothesis that the aryl hydrocarbon receptor (AhR) is a physiological regulator of HSCs. These data support the contention that AhR acts as a negative regulator by curbing excessive or unnecessary proliferation and promoting HSC quiescence. While our lab has done much work to understand the biology associated with AhR disruption in HSCs, we have not yet identified AhR-regulated signaling pathways that define normal HSC function as well as play a role in altered function under conditions of AhR dysregulation. We hypothesize that the Wnt and/or HIF signaling pathways are critical for AhR-mediated regulation of HSCs. We also hypothesize that dysregulation of AhR expression in HSCs, through disruption of these pathways, results in accumulation of oxidative DNA damage that eventually restricts self-renewal and causes premature senescence. Using a combination of molecular and cell biology techniques, unique animal models, and signaling pathway analyses, we will determin AhR-regulated signaling pathways in HSCs that define AhR function and that may lead to, under conditions of dysregulation, to HSC senescence and hematopoietic disease.

描述（由申请人提供）：造血干细胞（HSC）具有自我更新和分化为所有血统的能力。精确地维持静止，自我更新，增殖和分化之间的平衡，以在整个生物体的寿命中以及对压力，组织损伤和病原体的反应过程中保留多条层次的生成。尽管HSC中这些过程的失调对人类健康具有巨大的影响，但如何理解这种平衡的调节方式。最近的数据支持了新的假设，即芳基烃受体（AHR）是HSC的生理调节剂。这些数据支持AHR通过遏制过度或不必要的增殖并促进HSC静止的观点。尽管我们的实验室已经做了很多工作来了解与HSC中AHR中断相关的生物学，但我们尚未确定AHR调节的信号传导途径，这些信号传导途径定义了正常的HSC功能，并且在AHR失调条件下在功能上起作用，在AHR失调条件下起作用。我们假设Wnt和/或HIF信号通路对于HSC的AHR介导的调节至关重要。我们还假设，通过破坏这些途径，HSC中AHR表达的失调导致氧化DNA损伤的积累，最终限制了自我更新并导致过早衰老。使用分子和细胞生物学技术，独特的动物模型和信号通路分析的结合，我们将确定AHR调节的HSC中定义AHR功能的信号通路，并可能导致HSC衰老和造血性疾病的失调条件。