Pathophysiology of Radiation-induced Bone Loss

描述（由申请方提供）：拟议研究的广泛目标是研究电离辐射诱导的骨丢失的病理生理学。暴露于治疗剂量的电离辐射的骨显示降低的矿物质密度、较差的机械强度、红骨髓的过早脂肪替代，并且易于发生功能不全骨折。电离辐射对骨骼干细胞（骨髓基质细胞（BMSC）的一个子集，也称为骨髓源性间充质干细胞）谱系定型的影响定义不清，需要进一步研究。该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骨形成活性。所提出的实验旨在检验辐射耗尽间充质祖细胞的成骨潜力并促进成脂分化作为替代命运的假设，以及BMSC的重建将减轻辐射骨的结构和代谢缺陷特征。这一假设将在三个特定的目标进行测试：（1）检查骨髓基质细胞衍生的骨祖细胞作为一个因素驱动辐射诱导的骨丢失的损耗;（2）评估P-PAR？作为放射性骨丢失的治疗靶点;和（3）评估BMSC作为放射性骨丢失的缓解剂的功效。这些目标将通过使用小鼠模型和细胞培养实验，结合遗传学，药理学和基于细胞的治疗策略来实现。进一步了解电离辐射对BMSC多谱系分化能力的不良影响可能会产生新的治疗靶点，用于预防和/或纠正放疗后可能发生的骨丢失。

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.