Salivary Biomarkers in the Diagnosis of BRONJ

描述(由申请者提供)：K02独立科学家奖的总体目标是扩大Aghaloo博士目前的研究计划，包括(1)以患者为导向的研究和统计方法的正式和非正式培训，(2)获得肿瘤学基础和临床科学的额外知识，以及(3)获得蛋白质组学和生物标记物的培训，以进行一项以患者为导向的探索性研究，以确定不同严重程度的BRONJ患者唾液中差异表达的蛋白质。她目前的R01拨款专注于双膦酸盐相关性颌骨坏死(BRONJ)的病理生理学，方法是研究双膦酸盐(BPS)抑制破骨细胞的体外机制，并利用临床相关的体内BRONJ动物模型。K02应用中的研究策略将通过对唾液蛋白质和多肽的探索性研究来扩展这些研究，以帮助诊断、监测和管理BRONJ患者。静脉BPS是治疗原发和转移性骨癌的常用药物。虽然BPS降低了骨折风险，减少了恶性肿瘤的高钙血症，但许多患者发生了ONJ。到目前为止，BRONJ的诊断一直是临床上的，通常结合放射学检查和活组织检查来确认坏死骨。治疗方法从警惕等待到药物治疗和保守清创，从高压氧到广泛的颌骨切除。这些治疗方式的结果通常是通过临床检查来评估的，但持续暴露和坏死骨的混淆与手术延迟伤口愈合之间的区别具有挑战性。在生物标志物时代，利用血清或唾液体液是帮助诊断、监测和评估治疗反应的一种有吸引力的方法。人的血浆和血清被广泛用于疾病诊断、监测和预后，血清图谱已经被很好地记录在各种癌症的高敏感性。最近，人类唾液蛋白质组分析已被证明对了解口腔健康和疾病发病机制具有重要意义。因此，研究策略的目标是确定和验证BRONJ诊断的候选唾液生物标记物，验证唾液生物标记物与BRONJ临床诊断相关的假设。为了实现我们的研究策略目标并验证我们的假设，我们提出了两个具体的目标：(1)从I-III期BRONJ癌症患者中鉴定唾液蛋白和多肽；(2)验证蛋白质组学结果，并开发用于I-III期BRONJ诊断的候选标记。除了确定与BRONJ相关的唾液生物标记物外，这笔赠款还将导致临床研究方面的培训和实践专业知识，以及建立肿瘤学、生物标记物和蛋白质组学基础设施，使Aghaloo博士能够设计未来的临床研究，无论是针对ONJ还是其他口腔疾病。

DESCRIPTION (provided by applicant): The overall goal of the K02 independent scientist award is to expand Dr. Aghaloo's current research program with (1) formal and informal training in patient-oriented research and statistical methodology, (2) to gain additional knowledge in the basic and clinical sciences of oncology, and (3) to obtain training in proteomics and biomarkers to perform an exploratory patient-oriented study to identify differentially expressed proteins in the saliva of BRONJ patients at different stages of severity. Her current R01 grant focuses on the pathophysiology of bisphosphonate related osteonecrosis of the jaws (BRONJ), by studying both in vitro mechanisms of osteoclast inhibition by bisphosphonates (BPs) and utilizing a clinically relevant in vivo BRONJ animal model. The research strategy in this K02 application will expand those studies with an exploratory study of salivary proteins and peptides to aid in diagnosis, monitoring, and management of BRONJ patients. Intravenous BPs are commonly used medications to treat primary and metastatic bone cancer. Though BPs reduce fracture risk and reduce hypercalcemia of malignancy, many patients develop ONJ. To date, diagnosis of BRONJ has been clinical, often combined with radiographic studies and biopsies to confirm necrotic bone. Therapy ranges from watchful waiting to medical therapy and conservative debridement to hyperbaric oxygen to extensive jaw resection. Outcomes of these treatment modalities are generally assessed by clinical examination, but confusion of continued exposed and necrotic bone vs. delayed wound healing from surgery are challenging to differentiate. In the era of biomarkers, utilizing serum or salivary body fluids is an attractive approach to aid in diagnosis, monitoring, and evaluating responses to treatment. Human plasma and serum is widely used in disease diagnosis, monitoring, and prognosis, and serum profiling has been well documented for various cancers with high sensitivity. More recently, human salivary proteome analysis has been shown to be important for understanding oral health and disease pathogenesis. Therefore, the objective of the research strategy is to identify and validate candidate salivary biomarkers for BRONJ diagnosis, testing the hypothesis that salivary biomarkers are associated with the clinical diagnosis of BRONJ. To achieve our research strategy objective and test our hypothesis, we propose two specific aims: (1) to identify saliva proteins and peptides from cancer patients with Stage I-III BRONJ and (2) to validate proteomics results and develop candidate markers for Stage I-III BRONJ diagnosis. In addition to identifying saliva biomarkers associated with BRONJ, this grant will result in training, hands-on expertise in clinical research, as well as the establishment of an oncology, biomarker, and proteomics infrastructure to allow Dr. Aghaloo to design future clinical studies, whether for ONJ or other oral diseases.