Development of the Cellular Biomarker for Diabetic Foot Ulcers

糖尿病足溃疡细胞生物标志物的开发

• 批准号: 7815650
• 负责人: HAROLD BREM
• 金额: $ 45.85万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815650
• 关键词: Address; Adjuvant; Amputation; Area; Biological Markers; Biological Markers; Biopsy; Caring; Cell Nucleus; Chronic; Clinic Visits; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Debridement; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Digital Photography; Disease; Epidermis; Failure; Funding; Future; Goals; Grant; Healed; Health Care Costs; Health system; Histopathology; Hospitalization; Human Resources; Immunohistochemistry; Impairment; Individual; Infection; Intervention; Laboratories; Lead; Limb structure; Lower Extremity; Measurement; Measures; Methods; Molecular; Monitor; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; New York; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Occupations; Osteomyelitis; Outcome; Outcome Measure; Pain; Patients; Phenotype; Pilot Projects; Proteins; Proto-Oncogene Proteins c-myc; Protocols documentation; Publications; Quality of life; Recruitment Activity; Research; Research Ethics Committees; Sampling; Science; Site; Skin; Skin Ulcer; Staging; Staining method; Stains; Stimulus; Students; Techniques; Time; Tissues; Translational Research; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Universities; Varicose Ulcer; Visit; Work; Wound Healing; base; c-myc Genes; cellular development; clinical Diagnosis; clinical phenotype; cost; design; diabetic patient; disability; disorder risk; evidence base; follow-up; graduate student; healing; high risk; improved; inhibitor/antagonist; interest; molecular marker; mortality; pressure; primary outcome; programs; prospective; protein expression; response; secondary outcome; soft tissue; standard care; standard of care; wound

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area 04, "Clinical Research" and two specific Challenge Topics: 03-DK-101, "Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest of NIDDK;" and 04-DK-102, "Improved techniques for clinical diagnosis, detailed clinical phenotyping, and clinical disease staging and activity for conditions of interest to NIDDK." The goal of this project is to identify objective, quantitative bio-molecular parameters that correlate with healing outcomes for diabetic foot ulcers (DFUs). Chronic non-healing DFUs are a widespread and serious clinical problem with high rates of morbidity, disability and mortality, including a high risk for lower limb amputations. About half of all DFUs fail to heal promptly or completely in response to the current standard of care. One of the major obstacles to prompt and complete DFU healing is the inability to predict which wounds are not likely to respond to standard treatment protocols and will require alternative interventions. The edges of chronic wounds contain tissue that expresses inhibitors of healing and does not respond to wound-healing stimuli. The challenge of this project is to develop a feasible quantitative method of distinguishing between tissue that has the capacity to heal and tissue that does not, thus identifying non-healing phenotype. This project proposes to identify biomarkers that can objectively and quantifiably identify non-healing tissue in DFUs. Two protein markers -- nuclear localization of ¿-catenin and induced expression of c-myc -- have been associated with healing impairment in other chronic wounds but have not been studied in DFUs. Therefore, the objective of this project is to determine whether expression of ¿-catenin and/or c-myc at the wound edge is correlated with objective quantitative measures of DFU wound closure. Fifty consecutive patients receiving the current standard of care for chronic DFUs will provide small wound tissue biopsies at the initial treatment (week 0) and 4 weeks later. The extent of wound closure at 4 weeks will be used as a surrogate outcome for wound healing and will be confirmed by histopathology. Aim 1 is to determine whether ¿-catenin localization in the nucleus is correlated with non-healing. ¿-catenin localization will be quantified by immunohistochemistry. The primary outcome measure will be the correlation between the extent of wound closure at week 4 and nuclear ¿-catenin staining. Aim 2 is to determine whether c-myc protein expression is correlated with non-healing. c-myc expression will be quantified by immunohistochemistry. The primary outcome measure will be the correlation between extent of wound closure and nuclear ¿-catenin staining. The secondary outcome measure will be the correlation between wound closure and expression of both markers together. This project is ideally suited to the goals of the NIH Challenge Initiative and the selected Challenge Topics because it advances the science of wound healing by identifying objective cellular biomarkers that predict healing outcomes and provides improved quantitative techniques that can be used to monitor treatment efficacy and clinical outcomes. This project has a high likelihood of achieving important milestones within two years because it is supported by an established and productive team of collaborators that has existing Institutional Review Board (IRB) approvals for DFU biopsy and analysis and has all of the methods and protocols validated and fully described in prior publications. Funds from this grant will create full-time and part- time jobs and support students to clinical and translational research. The long-term goal of this research program is to reduce the number of amputations and improve healing outcomes for millions of individuals suffering from the consequences of chronic non-healing skin ulcers. Successful completion of this project will result in identification of reliable biological markers that can be used to identify non-healing wound tissue and predict which diabetic foot ulcers are incapable of healing without timely and aggressive intervention.

描述（由申请人提供）：本申请涉及广泛的挑战领域 04“临床研究”和两个具体的挑战主题：03-DK-101“发现 NIDDK 感兴趣的疾病的疾病风险、进展或治疗反应的生物标志物”；和 04-DK-102，“改进的临床诊断技术、详细的临床表型分析以及 NIDDK 感兴趣的病症的临床疾病分期和活动。”该项目的目标是确定与糖尿病足溃疡 (DFU) 愈合结果相关的客观、定量的生物分子参数。慢性不愈合 DFU 是一个广泛而严重的临床问题，发病率、残疾率和死亡率很高，包括下肢截肢的高风险。根据目前的护理标准，大约一半的 DFU 无法迅速或完全治愈。 DFU 迅速和完全愈合的主要障碍之一是无法预测哪些伤口不太可能对标准治疗方案产生反应并且需要替代干预措施。慢性伤口的边缘含有表达愈合抑制剂的组织，并且对伤口愈合刺激没有反应。该项目的挑战是开发一种可行的定量方法来区分具有愈合能力的组织和不具有愈合能力的组织，从而识别非愈合表型。该项目旨在识别能够客观、定量地识别 DFU 中不愈合组织的生物标志物。两种蛋白质标记物——β-连环蛋白的核定位和 c-myc 的诱导表达——已与其他慢性伤口的愈合障碍相关，但尚未在 DFU 中进行研究。因此，该项目的目标是确定伤口边缘的 ¿-catenin 和/或 c-myc 表达是否与 DFU 伤口闭合的客观定量测量相关。连续 50 名接受当前慢性 DFU 标准护理的患者将在初始治疗（第 0 周）和 4 周后提供小伤口组织活检。 4 周时伤口闭合的程度将用作伤口愈合的替代结果，并由组织病理学证实。目标 1 是确定细胞核中 ¿-连环蛋白的定位是否与不愈合相关。 ¿-连环蛋白定位将通过免疫组织化学进行定量。主要结果指标是第 4 周伤口闭合程度与核 β-连环蛋白染色之间的相关性。目标 2 是确定 c-myc 蛋白表达是否与不愈合相关。 c-myc 表达将通过免疫组织化学进行定量。主要结果指标是伤口闭合程度与核 κ-连环蛋白染色之间的相关性。次要结果指标是伤口闭合与两种标记物表达之间的相关性。该项目非常适合 NIH 挑战计划和选定的挑战主题的目标，因为它通过识别预测愈合结果的客观细胞生物标志物来推进伤口愈合科学，并提供可用于监测治疗效果和临床结果的改进的定量技术。该项目很有可能在两年内实现重要的里程碑，因为它得到了成熟且富有成效的合作者团队的支持，该团队已获得 DFU 活检和分析的机构审查委员会 (IRB) 批准，并且所有方法和方案均在之前的出版物中经过验证和充分描述。这笔赠款的资金将创造全职和兼职工作，并支持学生进行临床和转化研究。该研究计划的长期目标是减少截肢次数并改善数百万患有慢性不愈合皮肤溃疡的患者的康复效果。该项目的成功完成将鉴定出可靠的生物标志物，这些标志物可用于识别不愈合的伤口组织，并预测哪些糖尿病足溃疡如果不及时和积极的干预就无法愈合。