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.

! 项目描述 肥胖是一种慢性的机体应激，影响多种生物功能和组织。肥胖及其 后遗症调节免疫系统和骨髓（BM）中的造血活性。值得注意的是， 肥胖与免疫功能的改变和肥胖的总体风险增加有关。 血液恶性肿瘤然而，尽管它们具有临床意义，肥胖的机制 影响造血系统的健康，并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健康的影响， 造血干细胞（HSC）区室。在Aim 1中，我们将研究细胞内在分子 这些机制使HSC能够科普肥胖引发的异常环境压力。基于 我们的初步结果，我们将集中在转录因子Gfi1，因为我们发现，上调这一点， 因子在调节肥胖症中HSC命运中至关重要。值得注意的是，我们发现了一种新的分子电路， HSC中的氧化应激和Gfi1表达。在这里，我们将确定潜在的分子机制 肥胖的联系。我们还将检验Gfi1上调影响细胞长期适应性的假设。 HSC通过调节它们的能力来进行适当的应激反应。在Aim2中，我们将在单个 细胞水平肥胖如何破坏HSC区室的稳态。我们将确定肥胖者 环境改变了HSC区室的分子和功能，克隆多样性，导致HSC的分化。 克隆造血的发展。最后，我们将检验肥胖环境可能 有利于携带肿瘤前特征的克隆的出现。总之，我们的研究将阐明 肥胖对血液系统的影响。他们将测试肥胖改变HSC的假设 内在的调节程序，影响HSC库的克隆结构，并促进前 白血病HSC克隆。这些研究将对我们理解 慢性肥胖对HSC区室健康的影响。在全球肥胖流行的情况下， 该项目的长期目标是破译与使用肥胖供体进行BM相关的潜在风险 干细胞移植和肥胖对肿瘤前期长期发展的影响 造血