Inflamm-aging of osteoprogenitor cells: A therapeutic target for improved bone healing

骨祖细胞的炎症老化：改善骨愈合的治疗靶点

• 批准号: 10803152
• 负责人: Philipp Leucht
• 金额: $ 34.75万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10803152
• 关键词: Adenosine; Adult; Affect; Age; Aging; Agonist; Animals; Anti-Inflammatory Agents; Apoptosis; Automobile Driving; Biological Assay; Bone Regeneration; Cell Aging; Cell Count; Cells; Chronic; Data; Deterioration; Down-Regulation; Elderly; Elements; Environment; Enzymes; Equilibrium; Feedback; Fracture; Functional disorder; Funding; Genetic Transcription; Homeostasis; Impaired cognition; Impairment; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Injury; Maintenance; Mediating; Molecular; Monitor; Multipotent Stem Cells; Mus; Musculoskeletal; Organ; Osteogenesis; Pathway Analysis; Pathway interactions; Population; Proliferating; Publishing; Quality of life; Receptors, Tumor Necrosis Factor, Type II; Regenerative capacity; Resolution; Role; Signal Pathway; Signal Transduction; Skeleton; Small Interfering RNA; Structure; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Time; Tissues; adult stem cell; age related; aged; bone; bone fracture repair; bone healing; bone health; bone preservation; bone repair; cell type; experimental study; extracellular; factor A; fracture risk; functional loss; gain of function; improved; in vivo; inflammatory milieu; insight; knock-down; lipid biosynthesis; loss of function; middle age; mortality risk; novel; novel therapeutics; older patient; osteogenic; osteoprogenitor cell; overexpression; prevent; progenitor; receptor; repaired; response; single-cell RNA sequencing; skeletal; skeletal stem cell; stem cell function; stem cell self renewal; stem cells; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Maintenance, remodeling, and repair of the adult body is mediated by multipotent stem cells that give rise to a variety of cell types that comprise the tissue in which they reside. During aging, there is a decline in homeostatic and regenerative capacity leading to progressive degeneration of the structure and function of vital organs. In particular, musculoskeletal degeneration is common in the elderly and leads to increased fracture risk and reduced efficiency of fracture repair that drastically decreases quality of life. Our previous studies showed that an age-associated increase in chronic, low-grade inflammation is the main cause of skeletal stem and progenitor cell (SSPCs) dysfunction. Thus, we hypothesize that reducing pro-inflammatory signals and enhancing anti- inflammatory activity will rescue SSPC number and osteogenic function in aged individuals. To investigate this, we will first precisely define the molecular mechanisms regulating the inflammatory response in SSPCs, and the role of anti-inflammatory factors in the resolution of inflammation. We will determine how these mechanisms and the interaction between opposing pro- and anti- inflammatory signals is affected by aging. These experiments will generate insights into the elements driving bone degeneration and identify therapeutic targets to improve bone health and fracture repair in elderly patients. Our strong preliminary experiments also identified two prime suspects involved in SSPC deterioration during aging. We will perform gain and loss of function experiments in SSPCs to elucidate their specific role in the control of stem cell self-renewal and differentiation. As manipulation of these factors can affect the extracellular inflammatory milieu, we will use single-cell RNA-sequencing to determine their cell-intrinsic function in SSPCs and also their influence on defined populations within the local niche. Finally, we will manipulate candidate expression following injury in aged animals to assess their ability to rescue stem cell regenerative capacity and improve bone healing.

项目摘要 成人身体的维持、重塑和修复是由多能干细胞介导的， 各种细胞类型，包括它们所在的组织。在衰老过程中，体内稳态 和再生能力，导致重要器官的结构和功能的进行性退化。在 特别是，肌肉骨骼退化在老年人中很常见，导致骨折风险增加， 骨折修复效率降低，生活质量急剧下降。我们之前的研究表明， 与年龄相关的慢性、低度炎症的增加是骨骼干细胞和祖细胞的主要原因。 细胞（SSPCs）功能障碍。因此，我们假设，减少促炎信号和增强抗- 炎症活性将挽救老年个体中SSPC数量和成骨功能。为了调查这一点， 我们将首先精确地定义调节SSPC中炎症反应的分子机制， 以及抗炎因子在炎症消退中的作用。我们将确定这些 机制和相互作用之间的对立的促炎和抗炎信号是受老化。 这些实验将深入了解导致骨退化的因素， 治疗目标是改善老年患者的骨健康和骨折修复。我们强大的初步 实验还确定了两个主要嫌疑人参与SSPC老化过程中的恶化。我们将执行 SSPC功能获得和丧失实验，以阐明其在干细胞调控中的特定作用 自我更新和分化。由于这些因素的操纵可以影响细胞外炎症反应， 在这种情况下，我们将使用单细胞RNA测序来确定它们在SSPCs中的细胞内在功能，以及它们在SSPCs中的表达。 对当地生态位内特定人群的影响。最后，我们将操作候选表达式 在老年动物受伤后，评估其拯救干细胞再生能力的能力， 促进骨愈合。