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

钙卫蛋白作为伤口愈合中的分子传感器和氧化调节剂

• 批准号: 7933267
• 负责人: Herve Y Sroussi
• 金额: $ 9.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933267
• 关键词: Address; Advisory Committees; Affect; Aging; Award; Biological; Biology; Calgranulin B; Cell Proliferation; Cells; Clinical Research; Cutaneous; Dentistry; Development; Diabetes Mellitus; Endothelial Cells; Engineering; Environment; Equipment; Ethics; Experimental Models; Faculty; Fibroblasts; Foundations; Funding; Grant; Growth; Healed; Health Sciences; Impaired wound healing; In Vitro; Inflammation; Inflammatory Response; Kinetics; Knowledge; Leukocyte L1 Antigen Complex; Leukocytes; Medical; Mentors; Metabolic; Metabolism; Modeling; Molecular; Monitor; Mus; Oral health; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Physiological; Process; Production; Reactive Oxygen Species; Recombinants; Research; Research Personnel; Research Project Grants; Respiratory Burst; Role; S100A8 gene; Speed; Stress; Testing; Therapeutic; Tissues; Training; Work; Wound Healing; angiogenesis; antimicrobial; college; healing; improved; in vivo; member; molecular marker; mouse model; neutrophil; oxidation; programs; protein complex; restraint; restraint stress; sensor; therapeutic target; wound

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.

描述（由申请人提供）：本申请的目的是让 Sroussi 博士扩大他的博士培训，并为作为终身教授的自我维持的长期研究计划奠定基础。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 (Phillip Marucha) 博士将在成为一名成功的独立研究教师的各个方面为候选人提供指导，包括：制定国际认可的竞争性研究项目；显着提高口腔健康科学知识；在跨学科团队内合作；并最终获得项目资助（R01）以支持独立研究团队。该计划还将包括研究道德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，包括设备使用、配套启动资金以及综合学术健康科学中心内丰富的培育研究环境。 Sroussi 博士建议以他之前关于钙卫蛋白的研究为基础，钙卫蛋白是一种多效性且功能上非冗余的蛋白质复合物，在伤口愈合过程中高度表达。他将研究其氧化作用，并在压力受损伤口愈合的实验模型中测试其相关性，在该模型中，氧气的作用先前已确定。该模型中的氧化还原失衡会导致氧化应激，从而可能引发有害炎症、代谢失调、血管生成不足和伤口愈合受损。其他人完成并由 Sroussi 博士扩展的工作表明，钙卫蛋白以其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。研究假设是钙卫蛋白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解决钙卫蛋白及其氧化对伤口愈合两个关键方面的影响：中性粒细胞氧化爆发，这对于抗菌活性很重要；以及分解代谢细胞的增殖，这对于替换受损组织非常重要。该提案的第三个目标将通过在已建立的约束应激小鼠模型中测试不同氧化条件下钙卫蛋白对伤口愈合的影响，直接解决钙卫蛋白的生物学相关性。在该模型中，约束会损害伤口的氧气供应，导致氧化应激和愈合改变。将测试氧化钙卫蛋白分子加速伤口愈合和消除束缚应力影响的能力。了解钙卫蛋白在氧化还原生物学中的作用将有助于开发具有广泛有益医学影响的靶向治疗方法。衰老、糖尿病或压力会导致伤口供氧不足，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。

项目成果

The down regulation of neutrophil oxidative metabolism by S100A8 and S100A9: implication of the protease-activated receptor-2.

• DOI: 10.1016/j.molimm.2011.12.001
• 发表时间: 2012-02
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Sroussi HY;Lu Y;Villines D;Sun Y
• 通讯作者: Sun Y

S100A8 and S100A9 inhibit neutrophil oxidative metabolism in-vitro: involvement of adenosine metabolites.

• DOI: 10.3109/10715760903431434
• 发表时间: 2010-04
• 期刊: Free radical research
• 影响因子: 3.3
• 作者: Sroussi HY;Lu Y;Zhang QL;Villines D;Marucha PT
• 通讯作者: Marucha PT

Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

• DOI: 10.1016/j.bbi.2009.03.006
• 发表时间: 2009-08
• 期刊: BRAIN BEHAVIOR AND IMMUNITY
• 影响因子: 15.1
• 作者: Sroussi, Herve Y.;Williams, Richard L.;Zhang, Qing L.;Villines, Dana;Marucha, Phillip T.
• 通讯作者: Marucha, Phillip T.

The anti-oxidative, anti-inflammatory, and protective effect of S100A8 in endotoxemic mice.

• DOI: 10.1016/j.molimm.2012.10.002
• 发表时间: 2013-04
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Sun Y;Lu Y;Engeland CG;Gordon SC;Sroussi HY
• 通讯作者: Sroussi HY