CALPROTECTIN AS A MOLECULAR SENSOR AND REGULATOR OF OXIDATION IN WOUND HEALING

描述（由申请人提供）：本申请的目的是为Sroussi博士扩展他的博士培训，并为作为终身教职员工的自我维持，长期研究项目奠定基础。该奖项的培训方面将在导师和咨询委员会的指导下进行。菲利普·马鲁查博士将指导候选人成为一名成功的独立研究教师的各个方面，包括：开发国际公认的有竞争力的研究项目；显著提高口腔健康科学知识；与跨学科团队合作；并最终获得项目拨款（R01），以支持一个独立的研究团队。该计划还将包括研究伦理行为和临床研究方面的正式和实践培训。牙科学院将提供全方位的额外支持，包括获得设备，匹配的启动资金，以及一个综合性学术健康科学中心内丰富的培育研究环境。Sroussi博士建议建立在他之前关于钙保护蛋白的研究基础上，钙保护蛋白是一种多效性和功能上的非冗余蛋白复合物，在伤口愈合过程中高度表达。他将研究它的氧化作用，并在一个应力损伤伤口愈合的实验模型中测试它的相关性，在这个模型中，氧的作用是先前建立的。该模型中的氧化还原失衡导致氧化应激，从而引发有害炎症、代谢失调、血管生成缺陷和伤口愈合受损。由其他人完成并由Sroussi博士扩展的研究表明，钙保护蛋白以一种由自身氧化状态控制的方式调节氧化、白细胞募集和细胞代谢。研究假设钙保护蛋白是一种影响伤口愈合结果的氧化还原条件的分子传感器。该研究项目将在其前两个目标中解决钙保护蛋白及其氧化对伤口愈合的两个关键方面的影响：中性粒细胞氧化破裂，这在抗菌活性中很重要；以及分解代谢细胞的增殖，这对替换受损组织很重要。本提案的第三个目的是通过在已建立的小鼠约束应激模型中测试其在不同氧化条件下对伤口愈合的影响，直接解决钙保护蛋白的生物学相关性。在这个模型中，抑制损害了伤口的氧气供应，导致氧化应激和改变愈合。氧化钙保护蛋白分子加速伤口愈合和消除约束应力影响的能力将被测试。了解钙保护蛋白在氧化还原生物学中的作用将导致具有广泛有益医学影响的靶向治疗的发展。衰老、糖尿病或压力导致伤口供氧不足，导致愈合缓慢或失败。我们正在研究这一观察结果，并测试一种改善伤口愈合的策略。

DESCRIPTION (provided by applicant): The objective of this application is for Dr. Sroussi to expand on his doctoral training and lay the foundation for a self-sustaining, long-term investigational program as a tenure-track faculty member. The training aspect of the award will be under the guidance of a mentor and an advisory committee. Dr. Phillip Marucha will mentor the candidate in all aspects of becoming a successful independent research faculty including: developing an internationally recognized competitive research program; significantly advancing knowledge in Oral Health Science; collaborating within an interdisciplinary team; and ultimately obtaining a project grant (R01) to support an independent research team. This program will also include formal and practical training in the ethical conduct of research, and clinical research. The College of Dentistry will provide a full range of additional support including access to equipment, matching start-up funds, as well as a rich nurturing research environment within a comprehensive academic health sciences center. Dr. Sroussi proposes to build upon his previous work on calprotectin, a pleiotropic and functionally non-redundant protein complex that is highly expressed during wound healing. He will study its oxidation and test its relevance in an experimental model of stress-impaired wound healing in which the role of oxygen was previously established. Redox imbalance in this model results in oxidative stress which may trigger deleterious inflammation, metabolic deregulation, deficient angiogenesis and impaired wound healing. Work done by others and expanded by Dr. Sroussi has shown that calprotectin regulates oxidation, leukocyte recruitment and cell metabolism in a manner controlled by its own oxidative state. The study hypothesis is that calprotectin is a molecular sensor of redox conditions which influences the outcomes of wound healing. The research project will address in its first two aims the effects of calprotectin and its oxidation over 2 crucial aspects of wound healing: the neutrophil oxidative burst, which is important in antimicrobial activity; and the proliferation of catabolic cells, which is important in replacing damaged tissue. The third aim of this proposal will directly address the biological relevance of calprotectin by testing its effect under different oxidative conditions on wound healing in an established mouse model of restraint stress. In this model restraint impairs oxygen supply to the wound, resulting in oxidative stress and altered healing. The ability of oxidized calprotectin molecules to accelerate wound healing and eliminate the effect of restraint stress will be tested. Understanding the role of calprotectin in the context of redox biology will result in the development of targeted therapeutics with broad beneficial medical impact. Aging, diabetes or stress results in poor oxygen supply to wounds and in slow or failed healing. We are studying this observation and testing a strategy to improve wound healing.