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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：
9236188
负责人：
Kameshwar P Singh
金额：
$ 34.54万
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/9236188
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 Critical Pathways 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 response Immune system Incidence Knockout Mice Laboratories Lead Literature Malignant Neoplasms Mediating Molecular Biology Organism Pancytopenia Pathway Analysis 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 WNT Signaling Pathway Work Xenobiotics base cancer therapy leukemia leukemogenesis member novel oxidative DNA damage oxidative damage pathogen permissiveness premature public health relevance receptor expression receptor function regenerative response self-renewal senescence stem cell biology stem cell population stressor 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（申请人提供）：造血干细胞（HSC）具有自我更新和分化为所有血液谱系的能力。静止、自我更新、增殖和分化之间的平衡被精确地维持，以在生物体的整个生命周期中以及在对应激、组织损伤和病原体的响应期间保持多谱系世代。尽管HSC中这些过程的失调对人类健康有着巨大的影响，但这种平衡是如何调节的还不清楚。最近的数据支持新的假设，芳烃受体（AhR）是一个生理调节HSC。这些数据支持AhR通过抑制过度或不必要的增殖和促进HSC静止而作为负调节剂的论点。虽然我们的实验室已经做了很多工作来了解与HSC中AhR破坏相关的生物学，但我们尚未确定AhR调节的信号通路，这些信号通路定义了正常的HSC功能，并在AhR失调条件下改变功能中发挥作用。我们假设Wnt和/或HIF信号通路对于AhR介导的HSC调控至关重要。我们还假设，通过破坏这些通路，HSC中AhR表达的失调导致氧化DNA损伤的积累，最终限制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组合，我们将确定在HSC中AhR调节的信号通路，其定义AhR功能，并且在失调的条件下可能导致HSC衰老和造血疾病。