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

描述(由申请者提供)：此申请的目标是Sroussi博士扩展他的博士培训，并为作为终身教员的自给自足的长期研究计划奠定基础。该奖项的培训方面将在一名导师和一个咨询委员会的指导下进行。Phillip Marucha博士将在成为一名成功的独立研究人员的各个方面指导候选人，包括：开发国际公认的竞争性研究计划；显著提高口腔健康科学方面的知识；在跨学科团队中进行合作；以及最终获得项目拨款(R01)以支持独立研究团队。该计划还将包括在研究和临床研究的道德行为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、配套的启动资金，以及在一个综合学术健康科学中心内提供丰富的养育研究环境。Sroussi博士建议在他之前研究钙保护素的基础上再接再厉，钙保护素是一种多功能的非冗余蛋白质复合体，在伤口愈合过程中高度表达。他将研究它的氧化，并在一个应激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，氧气的作用是先前确定的。在这个模型中，氧化还原失衡导致氧化应激，可能引发有害的炎症、代谢紊乱、血管生成不足和伤口愈合障碍。其他人所做并经Sroussi博士扩展的研究表明，钙保护素以一种受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。研究假设是，钙保护素是氧化还原条件的分子传感器，影响伤口愈合的结果。该研究项目的前两个目标将涉及钙保护素及其氧化对伤口愈合的两个关键方面的影响：中性粒细胞氧化爆发，这在抗菌活性中很重要；以及分解代谢细胞的增殖，这对修复受损组织很重要。这项建议的第三个目的将通过在已建立的束缚应激小鼠模型中测试其在不同氧化条件下对伤口愈合的影响来直接解决钙保护素的生物学相关性。在这个模型中，束缚损害了伤口的氧气供应，导致氧化应激和愈合改变。将测试氧化的钙保护素分子加速伤口愈合和消除束缚压力的影响的能力。了解钙保护素在氧化还原生物学背景下的作用将导致具有广泛有益医学影响的靶向疗法的发展。衰老、糖尿病或压力会导致伤口氧气供应不足，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.