Manipulating Adipose Genes to Improve Bone Healing

操纵脂肪基因以改善骨骼愈合

• 批准号: 9250641
• 负责人: FREDRIC B. KRAEMER
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250641
• 关键词: Address; Adipocytes; Adipose tissue; Age; Aging; Alpha Cell; Biochemical; Blood Cells; Blood Circulation; Bone Density; Bone Growth; Bone Injury; Bone Marrow; Bone Marrow Stem Cell; Bone Regeneration; Bone Transplantation; Calvaria; Cartilage; Cell Lineage; Cell Therapy; Cells; Cellular biology; Chondrocytes; Defect; Dimensions; Environment; Evaluation; Fatty Acids; Fibroblasts; Fracture; Fracture Healing; Future; Generations; Genes; Goals; Growth; Growth Factor; Health; Healthcare Systems; Hematopoietic stem cells; Human; Hydrolysis; Impaired wound healing; Implant; Incidence; Inflammation Mediators; Injury; Investigation; Knockout Mice; Lead; Ligands; Lipase; Lipids; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolic Pathway; Metabolism; Methods; Minor; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Operative Surgical Procedures; Osteoblasts; Osteoporosis; Oxides; PPAR gamma; Pain; Physiological; Population; Positioning Attribute; Process; Quality of life; Research Personnel; Site; Speed; Stem cells; Stromal Cells; Testing; Time; Trauma; Triglycerides; Work; X-Ray Computed Tomography; adipocyte differentiation; bone; bone cell; bone healing; bone mass; clinical investigation; clinical translation; experimental study; extracellular; healing; implantation; improved; in vivo; knock-down; lipid biosynthesis; membrane synthesis; microCT; novel strategies; osteoblast differentiation; osteogenic; pre-clinical; productivity loss; public health relevance; receptor; repository; stem; stem cell differentiation; sterol esterase; tool; transcription factor

 DESCRIPTION (provided by applicant): It is estimated that there are almost 16 million bone fractures in the U.S. each year. While many of these fractures occur following trauma, an increasing number of fractures occur with only minor trauma as the incidence of osteoporosis increases and the population ages. In particular, aging is associated with poorer healing. Thus, fracture and healing have a substantial impact on overall health, mobility, quality of life, and the health care system. Although most fractures heal normally or with minimal surgical intervention, approximately 5-15% of fractures display delayed healing or nonunion. When nonunion occurs, it is associated with significant morbidity, prolonged pain, additional surgical procedures, reductions in the quality of life and loss of productivity. Cell-based therapies for bone healing, particularly the use of mesenchymal stem or stromal cells (MSCs) that can differentiate into osteoblasts, adipocytes and chondrocytes, have been the focus of preclinical and clinical investigation and represent an attractive adjunct to current standard methods. Studies have shown what appears to be an inverse relationship between the differentiation of MSCs along either an adipocyte or osteoblast lineage such that agents that stimulate adipocyte differentiation simultaneously inhibit osteoblast differentiation and, conversely, agents that stimulate osteoblast differentiation simultaneously inhibit adipocyte differentiation. The overall goal of this proposal is to take advantage of the known interplay between adipose cells and osteoblasts by manipulating specific genes involved in adipose metabolism to favor the differentiation of MSCs into bone and, thus, accelerate bone healing following injury. Specific aim #1 will test the hypothesis that global knockdown of hormone sensitive lipase (HSL) will accelerate bone healing in mice using a bone injury model that recapitulates fracture healing. This will be accomplished by comparing the ability of wild-type control mice and HSL null mice to heal a tibial injury model that creates a non-critical bone defect. Specific aim #2 will examine the impact of knockdown of HSL in bone marrow MSCs on bone healing in mice with a critical bone injury model. This will be accomplished by comparing the ability of bone grafts derived from bone marrow isolated from either wild-type control mice or HSL null mice to accelerate bone healing when implanted into mice with a calvarial bone injury model that will not heal without implantation. Successful completion of this SPiRE will lay the groundwork for a full RR&D Merit proposal that will explore the biologic basis for this approach in more detail and further evaluate the potential for its clinical translation.

 描述（由申请人提供）： 据估计，美国每年有近1600万例骨折。虽然这些骨折中的许多发生在创伤后，但随着骨质疏松症的发病率增加和人口老龄化，越来越多的骨折仅在轻微创伤下发生。特别是，衰老与较差的愈合有关。因此，骨折和愈合对整体健康、活动能力、生活质量和医疗保健系统有重大影响。虽然大多数骨折会愈合 正常情况下或在最小手术干预下，约5-15%的骨折显示延迟愈合或不愈合。当骨不连发生时，它与显著的发病率、长期疼痛、额外的外科手术、生活质量降低和生产力丧失有关。用于骨愈合的基于细胞的疗法，特别是使用可分化成成骨细胞、脂肪细胞和软骨细胞的间充质干细胞或基质细胞（MSC），已经成为临床前和临床研究的焦点，并且代表了对当前标准方法的有吸引力的辅助。研究表明，MSC沿脂肪细胞或成骨细胞谱系沿着分化之间似乎存在反比关系，使得刺激脂肪细胞分化的试剂同时抑制成骨细胞分化，相反，刺激成骨细胞分化的试剂同时抑制脂肪细胞分化。该提案的总体目标是利用脂肪细胞和成骨细胞之间已知的相互作用，通过操纵参与脂肪代谢的特定基因来促进MSC分化为骨骼，从而加速损伤后的骨骼愈合。具体目标#1将使用再现骨折愈合的骨损伤模型来检验激素敏感脂肪酶（HSL）的整体敲低将加速小鼠中的骨愈合的假设。这将通过比较野生型对照小鼠和HSL缺失小鼠愈合产生非关键性骨缺损的胫骨损伤模型的能力来实现。具体目标#2将检查骨髓MSC中HSL的敲低对具有严重骨损伤模型的小鼠中骨愈合的影响。这将通过比较源自从野生型对照小鼠或HSL缺失小鼠分离的骨髓的骨移植物在植入具有颅骨骨损伤模型的小鼠中时加速骨愈合的能力来实现，所述颅骨骨损伤模型在不植入的情况下将不会愈合。SPiRE的成功完成将为完整的RR&D Merit提案奠定基础，该提案将更详细地探索这种方法的生物学基础，并进一步评估其临床转化的潜力。