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）：血细胞生成受损与发病率和死亡率相关。随着造血干细胞（hsc）通过toll样受体（TLRs）直接感知病原体并对其做出反应的意想不到的认识，经典的血细胞补充模型正在发生变化。在TLR刺激下，小鼠造血干细胞增殖并优先进行骨髓特异性分化。直接感知TLR配体被认为能够使造血干细胞立即补充在急性感染期间迅速耗尽的先天免疫细胞。与短期HSC激活的潜在益处相反，慢性