Regulation of Human Mast Cell Function

描述(由申请人提供)：赵博士的长期目标是发展成为一名独立的内科科学家，具备识别研究机会的技能和成熟的能力，并构建合理的基础和可实现的战略来应对这些机会。高级课程和辅导的结合应该会让这成为可能。劳伦斯·B·施瓦茨博士将担任导师。赵医生最近加入了VCU，从2003年7月开始担任儿科学助理教授。在儿科内提供了研究空间以及工资支持和受保护的时间。 人的肥大细胞是获得性免疫的效应细胞，可能是先天免疫的效应细胞。它们在血管周围以及皮肤、胃肠道和肺组织中大量存在。获得高纯度的人皮肤来源的肥大细胞并在培养中增殖并保留原始肥大细胞的功能表型的能力为此类细胞的研究提供了关键的工具。目前的建议将研究这些肥大细胞和细胞因子之间的关系，以及这些肥大细胞在慢性荨麻疹发病机制中的作用。目的1研究通过FcepsilonRI激活的人皮肤来源的肥大细胞产生的细胞因子和脂质介质。由于初步结果表明，许多细胞因子在释放过程中或释放后不久被降解，推测是由共同释放的肥大细胞蛋白酶造成的，因此将开发条件来防止它们的降解，从而充分认识它们的产生。目的研究细胞因子通过IgE和Ig G受体激活的肥大细胞调节细胞因子产生和前列腺素和白三烯产生的能力。目的3将表征慢性荨麻疹患者的血清标记人类皮肤肥大细胞表面和激活或启动人类皮肤来源肥大细胞的能力。了解人类肥大细胞的这些功能属性将为过敏性疾病的发病机制提供洞察力，并可能揭示新的治疗靶点。

DESCRIPTION (provided by applicant): The long-term goal is for Dr. Zhao to develop as an independent physician scientist with the skill and maturity to identify research opportunities and to construct rationale and achievable strategies to address these opportunities. The combination of advanced coursework and mentoring should make this possible. Dr. Lawrence B. Schwartz will serve as mentor. Dr. Zhao recently joined the VCU as an Assistant Professor of Pediatrics beginning July, 2003. Research space has been provided within the Department of Pediatrics along with salary support and protected time. Human mast cells are effector cells of acquired and probably innate immunity. They are abundant around blood vessels and in cutaneous, gastrointestinal and pulmonary tissues. The ability to obtain human skin-derived mast cells of high purity that proliferate in culture and retain the functional phenotype of the original mast cells provides a critical tool for research on such ceils. The current proposal will examine relationships between these mast cells and cytokines, and the role of such mast cells in the pathogenesis of chronic urticaria. Aim 1 will characterize the cytokines and lipid mediators produced by human skin-derived mast cells activated through FcepsilonRI. Because preliminary results indicate many of the cytokines are degraded during or shortly after their release, presumably by co-released mast cell proteases, conditions will be developed to prevent their degradation and thereby appreciate the full extent of their production. Aim 2 will examine the ability of cytokines to regulate cytokine production and prostaglandin and leukotriene generation by mast cells activated through IgE and IgG receptors. Aim 3 will characterize the ability of sera from patients with chronic urticaria to label the surface of and to activate or prime human skin-derived mast cells. Understanding these functional attributes of human mast cells will provide insights into the pathogenesis of allergic disease and may reveal new therapeutic targets.