Pathophysiology of Radiation-induced Bone Loss

辐射引起的骨丢失的病理生理学

• 批准号: 9232300
• 负责人: Jason Andrew Horton
• 金额: $ 24.9万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232300
• 关键词: Adipocytes; Adverse effects; Animal Experiments; Apoptosis; Architecture; Automobile Driving; Blood Vessels; Bone Marrow; Bone Tissue; Cancer Survivorship; Cell Culture Techniques; Cell Differentiation process; Cells; Characteristics; Development; Diagnosis; Dose; Engraftment; Etiology; Failure; Femur; Foundations; Fracture; Functional disorder; Genetic; Genetic Predisposition to Disease; Goals; Health; Hormones; Incidence; Inferior; Infiltration; Ionizing radiation; Learning; Leptin; Malignant Neoplasms; Marrow; Mechanics; Mentors; Mentorship; Mesenchymal Stem Cells; Metabolic; Metabolism; Minerals; Morbidity - disease rate; Mus; Necrosis; Obesity; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteopenia; Osteoradionecrosis; Outcome; Perfusion; Peroxisome Proliferators; Persons; Pharmaceutical Preparations; Physicians; Prevention; Radiation; Radiation Injuries; Radiation therapy; Red Marrow; Research; Research Personnel; Scientist; Series; Skeleton; Solid; Stem cells; Stromal Cells; Testing; Therapeutic; Thiazolidinediones; Time; adipocyte differentiation; adult stem cell; base; bone; bone healing; bone loss; cancer therapy; career; citrin; density; design; diabetic; experience; functional outcomes; in vitro Model; in vitro testing; in vivo; insight; irradiation; mouse model; new therapeutic target; novel; osteogenic; osteoprogenitor cell; precursor cell; premature; progenitor; prophylactic; radiation effect; receptor; reconstitution; research study; senescence; skeletal; skeletal tissue; stem; stem cell population; stem cell therapy; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The broad goal of the proposed research is to investigate the pathophysiology of bone loss induced by ionizing radiation. Bones exposed to therapeutic doses of ionizing radiation display reduced mineral density, inferior mechanical strength, premature fatty replacement of red marrow, and are predisposed to insufficiency fractures. The effects of ionizing radiation on the lineage commitment of skeletal stem cells (a subset of marrow stromal cells (BMSCs) also known as bone marrow derived mesenchymal stem cells) is poorly defined, and warrants further study. The experiments that are described in the proposal will determine how radiation impacts the development and cumulative bone forming activity of the osteoblast and its precursor cells. The proposed experiments are designed to test the hypothesis that radiation depletes the osteogenic potential of mesenchymal progenitor cells and promotes adipogenic differentiation as an alternate fate, and that reconstitution of BMSCs will mitigate the structural and metabolic deficits characteristic of irradiated bone. This hypothesis will be tested in three specific aims: (1) Examine depletion of BMSC-derived osteoprogenitors as a factor driving radiation-induced bone loss; (2) Assess P-PAR? as a therapeutic target in radiation-induced bone loss; and (3) Evaluate efficacy of BMSC as a mitigant of radiation-induced bone loss. These aims will be accomplished through the use of mouse models and cell culture experiments in combination with genetic, pharmacologic and cell-based therapeutic strategies. Greater understanding of the adverse effects of ionizing radiation on the multi-lineage differentiation capacity of BMSC may yield new therapeutic targets for the prevention and/or correction of bone loss that may be experienced following radiotherapy.

描述(申请人提供)：拟议研究的主要目标是调查电离辐射引起的骨丢失的病理生理学。暴露在治疗性剂量的电离辐射下的骨骼显示出矿物质密度降低，机械强度降低，红骨髓脂肪过早替代，并容易发生不充分的骨折。电离辐射对骨骼干细胞(骨髓基质细胞(BMSCs)的一个亚群，也称为骨髓间充质干细胞)的谱系承诺的影响尚不清楚，值得进一步研究。提案中描述的实验将确定辐射如何影响成骨细胞及其前体细胞的发育和累积成骨活性。这些实验旨在验证一种假说，即辐射会耗尽间充质前体细胞的成骨潜能，并促进成脂分化作为另一种命运，而骨髓间充质干细胞的重建将缓解受照射骨的结构和代谢缺陷。这一假说将在三个具体目标上得到验证：(1)研究骨髓间充质干细胞来源的成骨细胞的枯竭是导致辐射导致骨丢失的一个因素；(2)评估P-PAR？作为放射性骨丢失的治疗靶点；以及(3)评价骨髓间充质干细胞作为放射性骨丢失的缓解剂的疗效。这些目标将通过使用小鼠模型和细胞培养实验，结合遗传、药理学和基于细胞的治疗策略来实现。更好地了解电离辐射对骨髓间充质干细胞多系分化能力的不利影响，可能为预防和/或纠正放射治疗后可能经历的骨丢失提供新的治疗靶点。