Mechanisms of TLR4-mediated impairment of murine and human HSC function

TLR4 介导的小鼠和人类 HSC 功能损伤的机制

• 批准号: 8635494
• 负责人: Lisa Borghesi
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635494
• 关键词: Acute; Address; Agonist; Animals; Bacteria; Bacterial Endocarditis; Biological; Blood; Blood Cells; Bone Marrow; Bromodeoxyuridine; Cell Aging; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Competence; Data; Disease; Dose; Equilibrium; Exhibits; Exposure to; Fatty Acids; Functional disorder; Gold; HIV; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homing; Human; Immune; Immune response; Impairment; In Vitro; Individual; Infection; Knowledge; Lead; Ligands; Link; Lipopolysaccharides; Lymphoid; Measures; Mediating; Metric; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Obese Mice; Obesity; Pancytopenia; Patients; Periodontal Diseases; Plasma; Pre-Clinical Model; Production; Proliferating; Publishing; Recombinant DNA; Signal Pathway; Signal Transduction; Site; Source; Stem cells; TLR4 gene; Testing; Therapeutic Intervention; Tissues; Toll-like receptors; Translating; base; cell age; clinically relevant; exhaust; exhaustion; human stem cells; in vivo; man; mimetics; mortality; mouse model; pathogen; premature; public health relevance; receptor; reconstitution; research study; self-renewal; stem; therapy development; toll-like receptor 4

DESCRIPTION (provided by applicant): Impaired production of blood cells is associated with morbidity and mortality. The classical model for blood cell replenishment is changing with the unexpected realization that hematopoietic stem cells (HSCs) directly sense and respond to pathogens via toll-like receptors (TLRs). Following TLR stimulation, murine HSCs proliferate and preferentially undergo myeloid-specific differentiation. Direct sensing of TLR ligand is thought to enable HSCs to immediately replenish innate immune cells that are rapidly depleted during acute infection. In contrast to the potential benefits of short-term HSC activation, chronic TLR stimulation dramatically impairs long-term HSC function. We have recently shown that murine HSCs chronically exposed to low-dose TLR4 agonist in vivo lose lymphoid potential, become exhausted, and fail to self renew. These findings are important because TLRs can be activated by endogenous fatty acids that are elevated in obesity as well as by plasma LPS or bacteria 16S rDNA which are present in patients with chronic infections. Like murine HSCs, in vitro studies show that human HSCs become activated and exhibit myeloid bias following TLR stimulation. However, the impact of TLR stimulation to human HSC function in vivo has not been established. Also unknown is the mechanism(s) by which chronic TLR stimulation perturbs HSC function. In Aim 1, we examine the impact of TLR4 stimulation to the self-renewal and multi-lineage reconstitution potential of human HSCs in vivo in a humanized mouse model. In Aim 2, we examine the mechanisms underlying TLR4-driven HSC skewing. These studies will be the first to establish the consequences of chronic TLR stimulation to human HSC competence in a pre-clinical model, and to establish the mechanism(s) by which TLR stimulation impairs HSC function.

描述（由申请人提供）：血细胞的产生受损与发病率和死亡率有关。血细胞补充的经典模型正在随着意外意识到直接感知造血干细胞（HSC）并通过Toll样受体（TLR）对病原体做出反应的意外情况。 TLR刺激后，鼠HSC增殖并优先经历髓样特异性分化。据认为，TLR配体的直接感知能够立即补充急性感染期间迅速消耗的先天免疫细胞。与短期HSC激活的潜在益处相反，慢性 TLR刺激极大地损害了长期HSC功能。我们最近表明，在体内长期暴露于低剂量TLR4激动剂中的鼠HSC失去了淋巴电势，变得筋疲力尽，无法自我更新。这些发现很重要，因为TLR可以通过肥胖症中升高以及血浆LPS或细菌16S rDNA升高的内源性脂肪酸激活，而慢性感染患者中存在。像鼠类HSC一样，体外研究表明，人类HSC被激活并在TLR刺激后表现出髓样偏置。但是，尚未建立TLR刺激对人体HSC功能的影响。慢性TLR刺激伴有HSC功能的机制也未知。在AIM 1中，我们研究了TLR4刺激对人类HSC在人源化小鼠模型中人体HSC的自我更新和多部位重构潜力的影响。在AIM 2中，我们检查了由TLR4驱动的HSC偏斜的机制。这些研究将是第一个在临床前模型中建立慢性TLR刺激对人HSC能力的后果，并确定TLR刺激会损害HSC功能的机制。