Development of Spectroscopic Biomarkers of Bone Quality in Metastatic Disease

转移性疾病骨质量光谱生物标志物的开发

• 批准号: 8076336
• 负责人: Xiaohong Bi
• 金额: $ 10.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076336
• 关键词: Aging; Animal Model; Apatites; Award; Biological; Biological Markers; Bioluminescence; Biomedical Research; Bone Matrix; Bone Pain; Bone Tissue; Bone neoplasms; Bone remodeling; Cancer Biology; Cardiac; Categories; Chemistry; Clinic; Collaborations; Collagen; Data; Development; Diagnosis; Diagnostic; Diagnostic radiologic examination; Discrimination; Disease; Educational workshop; Evaluation; Extracellular Matrix; Extramural Activities; Factor Analysis; Fiber Optics; Fracture; Funding; Future; Goals; Hand; Histology; Hypercalcemia; Image; Immunohistochemistry; In Situ; In Vitro; Injection of therapeutic agent; Knowledge; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measurement; Measures; Mentors; Metastatic Neoplasm to the Bone; Methodology; Methods; Modeling; Molecular; Molecular Structure; Monitor; Morbidity - disease rate; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Optics; Orthopedics; Osteoblasts; Osteoclasts; Osteolytic; Paralysed; Pathologic; Pathological fracture; Pattern Recognition; Primary Neoplasm; Principal Investigator; Property; Raman Spectrum Analysis; Research; Research Personnel; Research Project Grants; Resolution; Resources; Risk; Sampling; Serum; Site; Spatial Distribution; Spectrum Analysis; Statistical Models; Structure; Surgeon; System; Techniques; Testing; Therapeutic; Time; Tissue Harvesting; Tissues; Training; Treatment Cost; Tumor Burden; Universities; Woman; anticancer research; base; bone; bone cell; bone quality; bone turnover; cancer cell; cancer diagnosis; career; career development; environmental change; experience; improved; in vivo; interest; malignant breast neoplasm; medical specialties; men; mineralization; mouse model; non-invasive system; novel; novel strategies; outcome forecast; photonics; programs; public health relevance; response; skills; statistics; therapy development; tool; tumor; tumor progression; two-dimensional

DESCRIPTION (provided by applicant): The PI's long term career goal is to become an independent investigator in quantitative cancer research specializing in bone metastasis. The main research interest is to develop novel optical methodologies for cancer diagnosis or surgical guidance, and to develop/evaluate therapeutic treatments for bone metastasis. The immediate goals for the PI over the next four years are to obtain necessary trainings, gain experience in cancer photonics, establish independent research and build collaborations with the fellow colleagues. These goals will be achieved by realizing the following objectives 1) to enrich her knowledge in cancer biology, 2) to expand her specialty in the field of biomedical optics, 3) to pursue a serious research project from which she will gain experience in biomedical research and obtain preliminary data for future extramural funding, and 5) to establish collaborations and obtain other necessary trainings in career development through the research and educational resources at Vanderbilt University. The K25 award will allow the PI protected time to accomplish these goals by following a detailed training plan including hands on laboratory training in biological skills, several courses/workshop over the first two years, and a mentored research plan. For the proposed research project, the PI seeks to develop a statistical model that can be used in combination with Raman fiber optic probe, providing real-time quantitative assessment on the quality of metastatic bone in situ.This goal will be realized in three aims. Aim 1) Characterize the temporal alterations of metastatic bone in breast and prostate cancers using Raman spectroscopy. This aim will prove the overall hypothesis of the study that that the alterations in the quality of metastatic bone can be detected by Raman spectroscopy. Both lyitc and blastic metastases will be studied in an intra-cardiac and an intra-tibial injection mouse model for breast and prostate cancers, respectively. The structural and compositional properties of the bone matrix will be assessed for intact non-tumor and tumor-bearing bones using a fiber optic probe interfaced Raman spectroscopy. These Raman-derived bone quality measurements will be correlated with bone structure (by X-ray imaging and Micro-CT analysis), tumor burden (assessed by bioluminescence imaging in vivo), bone turnover (by serum biomarkers) and bone cell activities (by bone histomorphometry). Statistics evaluation will test whether bone quality is changed with the progression of tumor, and how the osteoblast/osteoclast activities and pathological bone turnover are related to the alterations in the quality of metastatic bone. Aim 2) Develop a statistical model that can provide real-time automated assessment on the quality of metastatic bone in situ. The full range of spectral data collected in Aim 1 will be analyzed using statistical pattern recognition method for extracting the diagnostic features and classifying them into corresponding categories of bone quality. Aim 3) Correlate Raman spectral biomarkers to the microenvironment of metastatic bone. This aim seeks to identify the biological contributors of the apparent spectral signatures (biomarkers) for metastatic bone. Two-Dimensional Raman maps will be acquired at the marked sites where Raman probe measurements are performed using conventional confocal Raman micro-spectroscopy with a spatial resolution at the cellular level. Multivariate factor analysis on the Raman maps can extract the spectrum and spatial distribution of each component (factor) in the sample. The molecular nature of each component will be identified by comparing its spectrum with that of model compounds. Additional guidance is available by comparing the image of factors with the immunohisto chemistry and bone histology images. Upon completion of this project, a quantitative spectral scoring system will be developed, which will enable in situ assessment for bone quality in metastasis when used in combination with Raman spectroscopy. This will provide the PI tools to establish her independent research in bone metastasis. The results will serve as preliminary data for the PI's future extramural funding application. PUBLIC HEALTH RELEVANCE: In this project, the PI seeks to develop a novel Raman spectroscopy method that can assess bone quality in metastatic disease in real time non-destructively. In clinics the correct assessment of bone quality is crucial to help orthopaedic surgeons evaluate bone damage caused by bone metastasis, while for treatment development, bone quality is an important determinant to evaluate the response of bone to therapy. Thus this project in the long run will help improve the diagnosis and prognosis of bone metastasis and limit treatment costs by avoidance of unnecessary tests.

描述（由申请人提供）：PI 的长期职业目标是成为专门从事骨转移的定量癌症研究的独立研究者。主要研究兴趣是开发用于癌症诊断或手术指导的新型光学方法，以及开发/评估骨转移的治疗方法。 PI 在未来四年的近期目标是获得必要的培训，获得癌症光子学方面的经验，建立独立研究并与同事建立合作。这些目标将通过实现以下目标来实现：1）丰富她在癌症生物学方面的知识，2）扩大她在生物医学光学领域的专业知识，3）开展认真的研究项目，从中她将获得生物医学研究经验并获得未来校外资助的初步数据，5）通过范德比尔特大学的研究和教育资源建立合作并获得职业发展方面的其他必要培训。 K25 奖项将允许 PI 受保护的时间通过遵循详细的培训计划来实现这些目标，包括生物技能实验室实践培训、前两年的多个课程/研讨会以及指导研究计划。 对于拟议的研究项目，PI 寻求开发一种可与拉曼光纤探针结合使用的统计模型，对原位转移骨的质量提供实时定量评估。这一目标将通过三个目标来实现。目标 1) 使用拉曼光谱表征乳腺癌和前列腺癌中转移性骨的时间变化。这一目标将证明该研究的总体假设，即可以通过拉曼光谱检测转移骨质量的变化。将分别在乳腺癌和前列腺癌的心脏内和胫骨内注射小鼠模型中研究lyitc和blast转移。将使用连接拉曼光谱的光纤探针来评估完整的非肿瘤和荷瘤骨的骨基质的结构和成分特性。这些拉曼衍生的骨质量测量将与骨结构（通过 X 射线成像和 Micro-CT 分析）、肿瘤负荷（通过体内生物发光成像评估）、骨转换（通过血清生物标志物）和骨细胞活动（通过骨组织形态计量学）相关。统计评估将检验骨质量是否随着肿瘤的进展而改变，以及成骨细胞/破骨细胞活性和病理性骨转换与转移骨质量的改变有何关系。目标 2) 开发一种统计模型，可以对原位转移骨的质量提供实时自动评估。目标 1 中收集的全系列光谱数据将使用统计模式识别方法进行分析，以提取诊断特征并将其分类为相应的骨质量类别。目标 3) 将拉曼光谱生物标志物与转移骨的微环境相关联。该目标旨在确定转移骨明显光谱特征（生物标志物）的生物贡献者。将在标记位点获取二维拉曼图，在这些位点使用具有细胞水平空间分辨率的传统共焦拉曼显微光谱进行拉曼探针测量。拉曼图上的多元因子分析可以提取样品中各成分（因子）的光谱和空间分布。通过将其光谱与模型化合物的光谱进行比较，可以识别每种成分的分子性质。通过将因子图像与免疫组织化学和骨组织学图像进行比较，可以获得额外的指导。 该项目完成后，将开发一个定量光谱评分系统，与拉曼光谱结合使用时，该系统将能够对转移中的骨质量进行原位评估。这将为她建立骨转移方面的独立研究提供 PI 工具。结果将作为PI未来校外资助申请的初步数据。 公共健康相关性：在该项目中，PI 寻求开发一种新型拉曼光谱方法，可以实时非破坏性地评估转移性疾病中的骨质量。在临床中，骨质量的正确评估对于帮助骨科医生评估骨转移引起的骨损伤至关重要，而对于治疗的发展，骨质量是评估骨对治疗反应的重要决定因素。因此，从长远来看，该项目将有助于改善骨转移的诊断和预后，并通过避免不必要的检查来限制治疗成本。