Project 3 - Role of SDF-1 in Age-Related changes in BMSC miRNA and Bone Loss

项目 3 - SDF-1 在 BMSC miRNA 和骨丢失的年龄相关变化中的作用

• 批准号: 9902287
• 负责人: Sadanand tukdoji Fulzele
• 金额: $ 33.51万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9902287
• 关键词: Affect; Age; Age-Related Bone Loss; Aging; Amino Acids; Applications Grants; Automobile Driving; Bone Marrow; Bone Marrow Stem Cell; Bone Tissue; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cell Survival; Cell physiology; Cells; Collaborations; Data; Diet; Dietary Intervention; Disease; Epigenetic Process; Extracellular Matrix; Family; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Homeostasis; Human; Impairment; In Vitro; Inflammation Mediators; Inflammatory; Lead; Ligands; Link; Mesenchymal; Methods; MicroRNAs; Molecular; Mus; Muscle; Nutrient; Nutritional; Osteogenesis; Osteoporosis; Outcome; Oxides; Pathway interactions; Plasma; Population; Protein Isoforms; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Stimulus; Stromal Cell-Derived Factor 1; System; Testing; Work; age related; bone; bone loss; bone mass; bone turnover; chemokine; cytokine; dietary manipulation; epigenetic regulation; genetic approach; improved; in vivo; mimetics; novel; novel therapeutics; osteogenic; osteoprogenitor cell; prevent; protein expression; stem; stem cells; therapeutic miRNA

The role of the cytokine SDF-1 (CXCL12) in bone marrow mesenchymal stem/progenitor cells (BMSCs) function and bone homeostasis was the focus of our previous work in the original PO1 Project 3. The novel outcomes from those studies are driving the current goals in this competitive renewal. The mechanisms involved in aging-related osteoporosis remain poorly defined, however, recent studies from our group, and others, suggest that it is a stem cell disease. A critical problem is that aging triggers impaired localization, proliferation, survival, and differentiation of the osteogenic progenitor cell population in the bone marrow (BM), specifically BMSCs. A critical barrier to preventing these changes is identifying key regulatory pathways, and being able to alter or correct them. Our goal is to use information generated from our original PO1, where we have identified epigenetic changes in a subset of miRNAs in BMSCs, and to target these miRNAs to limit, or reverse, bone loss. Age-associated changes in SDF-1 systemically alter epigenetic regulatory systems, specifically miRNAs, in BMSCs, which in turn directly, and via nutrient signaling pathways, affect cell survival, osteogenesis and bone formation. SDF-1 is tightly regulated translationally, transcriptionally, and post- transcriptionally. We have identified age-associated changes in the SDF-1 axis. Here we show that SDF-1 is not only a target of novel age-associated miRNA epigenetic regulation, but itself alters expression of miRNAs that change with age in BMSCs and target the SDF-1 axis. Significantly, a key miRNA that we identified to increase with age in BMSCs (miR-29b-1-5p) belongs to the miR29 family of miRNAs that have been shown to be critical in extracellular matrix homeostasis and osteogenesis. What is novel, and a challenge to the existing paradigm, is that miR29b-1-5p is the “passenger strand”, which is normally thought to be degraded leaving the complementary miR-29b-1-3p “guide strand” as the functional miRNA. Understanding the mechanism that drives this previously unknown age-associated increase in the passenger strand is a critical goal because we have demonstrated that miR29b-1-5p regulates SDF-1 expression and suppresses BMSC osteogenesis and survival pathways. We propose to test the hypothesis that the elevated age-related levels of circulating SDF-1 and decreased bone marrow compartment levels and activity regulate the increased expression of miR-29b-1- 5p and downstream effects on bone homeostasis. Our objectives are to test new hypotheses derived from the findings of the original PO1 by manipulating the miRNAs we identified as changing with age in human/murine BMSCs to determine their effects on bone formation and turnover in vivo and at the molecular level on BMSC osteogenic function. We will test novel methods to reduce expression of these miRNAs, including altering nutritional pathways leading to bone loss by using specific forms of dietary amino acid and delivering synthetic anti-miRNAs to inhibit them. The impact of this project will be demonstrating the role of age-associated changes of BMSC miRNAs and identifying novel targets for reducing, or reversing, age related bone loss.

细胞因子SDF-1（CXCL 12）在骨髓间充质干/祖细胞（BMSCs）中的作用 功能和骨稳态是我们以前在最初的PO 1项目3中的工作重点。小说 这些研究的结果正在推动这一竞争性更新的当前目标。的机制 然而，我们小组最近的研究， 其他人认为这是一种干细胞疾病。一个关键的问题是，老化触发受损的定位， 骨髓（BM）中成骨祖细胞群的增殖、存活和分化， 特别是BMSCs。防止这些变化的一个关键障碍是确定关键的调控途径， 能够改变或纠正它们。我们的目标是使用从原始PO 1生成的信息， 已经确定了BMSC中一组miRNAs的表观遗传变化，并靶向这些miRNAs以限制，或 相反，骨质流失。SDF-1中的突变相关变化系统性地改变表观遗传调节系统， 特别是BMSC中的miRNAs，其反过来直接并通过营养信号通路影响细胞存活， 骨生成和骨形成。SDF-1在转录、转录和转录后都受到严格调控。 转录。我们已经确定了SDF-1轴的年龄相关变化。在这里，我们表明SDF-1是 不仅是一个新的年龄相关的miRNA表观遗传调控的靶点， 随着年龄的增长而变化，并靶向SDF-1轴。值得注意的是，我们发现的一种关键的miRNA， BMSC中随年龄增加的miR-29 b-1- 5 p属于miR 29家族，已显示其 在细胞外基质稳态和骨生成中至关重要。什么是新颖的，什么是对现有的挑战 范例是，miR 29 b-1- 5 p是“乘客链”，通常认为它被降解，留下 互补的miR-29 b-1- 3 p“引导链”作为功能性miRNA。了解这种机制 推动这种以前未知的与年龄相关的乘客链增长是一个关键目标，因为我们 已经证明miR 29 b-1- 5 p调节SDF-1表达并抑制BMSC成骨， 生存之路。我们建议验证这一假设，即与年龄相关的循环SDF-1水平升高 降低的骨髓隔室水平和活性调节miR-29 b-1表达的增加。 5 p和下游对骨稳态的影响。我们的目标是测试新的假设来自 通过操纵我们鉴定为在人/鼠中随年龄变化的miRNAs， BMSC，以确定其对体内骨形成和骨转换的影响，并在分子水平上对BMSC 成骨功能。我们将测试新的方法来减少这些miRNAs的表达，包括改变 通过使用特定形式的膳食氨基酸和递送合成的 anti-miRNAs来抑制它们。该项目的影响将展示与年龄相关的 BMSC miRNAs的变化和鉴定用于减少或逆转年龄相关的骨丢失的新靶点。