Normal and Pathological Hematopoietic Stem Cells in Obesity

肥胖中的正常和病理性造血干细胞

• 批准号: 9905420
• 负责人: Damien Reynaud
• 金额: $ 39.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905420
• 关键词: Adipose tissue; Adverse effects; Affect; Autoimmune Diseases; Automobile Driving; Bar Codes; Biological Process; Blood Cells; Bone Marrow; Bone Marrow Stem Cell Transplantation; Cell Compartmentation; Cell physiology; Cells; Characteristics; Chronic; Clonal Hematopoietic Stem Cell; Complex; Development; Diet; Dysmyelopoietic Syndromes; Environment; Epidemic; GFI1 gene; Gene Expression Profiling; Genetic Transcription; Goals; Health; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell heterogeneity; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Hormonal; Immune system; Immunologics; Individual; Infection; Life; Link; Metabolic; Metabolism; Molecular; Mutation; Myeloproliferative disease; Obesity; Obesity Epidemic; Organ; Oxidative Stress; Pathogenicity; Pathologic; Population; Predisposition; Production; Risk; Stem cell transplant; Stress; Structure; System; Testing; Tissues; Up-Regulation; Work; base; biological adaptation to stress; clinically relevant; experimental study; fitness; global environment; hematopoietic stem cell fate; hematopoietic stem cell quiescence; immune function; in vivo; leukemia; leukemogenesis; neoplastic; novel; programs; response; transcription factor; transcriptome

! PROJECT DESCRIPTION Obesity is a chronic organismal stress that impacts multiple biological functions and tissues. Obesity and its sequelae modulate the immune system and the hematopoietic activity in the bone marrow (BM). Notably, obesity has been associated with altered immunological functions and an overall increased risk for hematological malignancies. However, despite their clinical relevance, the mechanisms by which obesity affects the health of the hematopoietic system and might contribute to its pathological dysregulation have yet to be characterized. Here, we seek to decipher the impact of obesity on the molecular and cellular fitness of the hematopoietic stem cell (HSC) compartment. In Aim1, we will investigate the cell-intrinsic molecular mechanisms that allow HSCs to cope with the aberrant environmental stresses triggered by obesity. Based on our preliminary results, we will focus on the transcriptional factor Gfi1 as we found that up-regulation of this factor is crucial in regulating HSC fate in obesity. Notably, we uncovered a novel molecular circuit that links oxidative stress and Gfi1 expression in HSCs. Here we will determine the molecular mechanisms underlying this link in obesity. We will also test the hypothesis that Gfi1 up-regulation affects the long-term fitness of the HSCs by modulating their ability to mount proper stress responses. In Aim2, we will investigate at the single cell level how obesity disrupts the homeostasis of the HSC compartment. We will determine whether the obese environment alters the molecular and functional, clonal diversity of the HSC compartment, leading to the development of a clonal hematopoiesis. Finally, we will test the hypothesis that the obese environment could favor the emergence of clones carrying pre-neoplastic features. Altogether, our studies will elucidate the impact of obesity on the hematological system. They will test the hypothesis that obesity alters the HSC intrinsic regulatory programs, affects the clonal structure of the HSC pool and promotes the emergence of pre- leukemic HSC clones. These studies stand to make critical contributions to our understanding of the adverse effects of chronic obesity on the health of the HSC compartment. In the midst of a global obesity epidemic, the long-term goal of this project is to decipher the potential risks associated with the use of obese donors for BM stem cell transplantation and the influence of obesity on the long-term development of pre-neoplastic hematopoiesis.

呢 项目描述 肥胖是一种慢性生物胁迫，会影响多种生物学功能和组织。肥胖及其 后遗症调节骨髓（BM）中的免疫系统和造血活性。尤其， 肥胖症与免疫功能的改变有关，总体上增加了 血液学恶性肿瘤。但是，尽管临床相关，但肥胖的机制 影响造血系统的健康，可能导致其病理失调 被描述。在这里，我们试图破译肥胖对分子和细胞适应性的影响 造血干细胞（HSC）室。在AIM1中，我们将研究细胞中性分子 允许HSC应对肥胖触发的异常环境应力的机制。基于 我们的初步结果，我们将重点关注转录因子GFI1，因为我们发现这是对此的上调 因子对于调节肥胖症中的HSC命运至关重要。值得注意的是，我们发现了一个新的分子电路 HSC中的氧化应激和GFI1表达。在这里，我们将确定基础的分子机制 肥胖中的这种联系。我们还将检验以下假设：GFI1上调影响了长期适应性 HSC通过调节其安装适当压力反应的能力。在AIM2中，我们将在单个中进行调查 细胞水平肥胖如何破坏HSC隔室的稳态。我们将确定肥胖是否 环境改变了HSC室的分子和功能性，克隆多样性，导致 克隆造血的发展。最后，我们将检验肥胖环境可以的假设 有利于携带可塑塑性特征的克隆的出现。总之，我们的研究将阐明 肥胖对血液学系统的影响。他们将检验肥胖改变HSC的假设 固有的调节计划会影响HSC池的克隆结构，并促进 白血病HSC克隆。这些研究将为我们对不利的理解做出重要贡献 慢性肥胖对HSC室健康的影响。在全球肥胖流行中， 该项目的长期目标是破译与使用BM使用肥胖捐助者有关的潜在风险 干细胞移植和肥胖对肿瘤前长期发展的影响 造血。