Salivary Biomarkers in the Diagnosis of BRONJ

描述（申请人提供）：K 02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志物方面的培训，以进行探索性的面向患者的研究，以鉴定处于不同严重程度阶段的BRONJ患者唾液中差异表达的蛋白质。她目前的R 01资助重点是双膦酸盐相关的颌骨骨坏死（BRONJ）的病理生理学，通过研究双膦酸盐（BPs）抑制破骨细胞的体外机制和利用临床相关的体内BRONJ动物模型。K 02申请中的研究策略将通过对唾液蛋白和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。静脉注射BP是治疗原发性和转移性骨癌的常用药物。虽然BPs可以降低骨折风险和降低恶性肿瘤的高钙血症，但许多患者会发生ONJ。迄今为止，BRONJ的诊断一直是临床的，通常结合放射学研究和活检来确认坏死的骨。治疗方法包括观察等待、药物治疗、保守性清创、高压氧和广泛的颌骨切除。这些治疗方式的结局通常通过临床检查进行评估，但持续暴露和坏死骨与手术延迟伤口愈合的混淆难以区分。在生物标志物时代，利用血清或唾液体液是一种有吸引力的方法，以帮助诊断，监测和评估对治疗的反应。人血浆和血清广泛用于疾病诊断、监测和预后，并且血清谱分析已被充分记录用于具有高灵敏度的各种癌症。最近，人类唾液蛋白质组分析已被证明是重要的了解口腔健康和疾病的发病机制。因此，研究策略的目的是鉴定和验证用于BRONJ诊断的候选唾液生物标志物，测试唾液生物标志物与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目标：（1）鉴定患有I-III期BRONJ的癌症患者的唾液蛋白和肽;（2）验证蛋白质组学结果并开发用于I-III期BRONJ诊断的候选标记物。除了确定与BRONJ相关的唾液生物标志物外，这笔赠款还将导致临床研究的培训，实践专业知识，以及建立肿瘤学，生物标志物和蛋白质组学基础设施，以允许Aghaloo博士设计未来的临床研究，无论是ONJ还是其他口腔疾病。 公共卫生相关性：颌骨骨坏死是一种与双膦酸盐使用相关的病态骨病。虽然发病率随着长期暴露于这些药物和合并症（包括化疗、牙科疾病和创伤）而增加，但没有经过验证的治疗方案存在，许多BRONJ患者遭受严重并发症，包括严重疼痛、肿胀、感染、瘘管和颌骨骨折，所有这些都显著影响患者的生活质量。由于人血浆/血清已被用于癌症诊断和预后多年，和人唾液最近已被证明是一种有价值的诊断流体，用于其他疾病，如艾滋病毒，口腔癌，和其他，我们建议确定潜在的生物标志物蛋白质在BRONJ患者的唾液。利用我们对BRONJ的基础和转化知识以及临床和唾液诊断研究专业知识，我们的目标是改善BRONJ或BRONJ风险患者的诊断，预防和管理。

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. PUBLIC HEALTH RELEVANCE: Osteonecrosis of the jaw is a morbid bone disorder associated with bisphosphonate use. Though the incidence is increasing with longer exposure to these medications and comorbidities including chemotherapy, dental disease, and trauma, no validated treatment protocols exist, and many BRONJ patients suffer significant complications including severe pain, swelling, infection, fistulae, and jaw fracture, all of which significantly impact patients' quality of life. Since human plasma/serum has been utilized for many years for cancer diagnosis and prognosis, and human saliva has recently proven to be a valuable diagnostic fluid for other diseases such as HIV, oral cancer, and others, we propose to identify potential biomarker proteins in the saliva of BRONJ patients. Utilizing our basic and translational knowledge of BRONJ and clinical and salivary diagnostic research expertise, our objectives are to improve diagnosis, prevention, and management of BRONJ or patients at risk for BRONJ.