INHIBITION OF MONOCYTE TGFB1-INDUCED SKIN FIBROSIS

候选人 Anita C. Gilliam 是凯斯西储大学 (CWRU) 皮肤科终身教授，她正在该校开展自身免疫性疾病分子机制的研究工作。 拟议的工作借鉴了她在分子生物学和皮肤免疫生物学方面的经验，并请求支持临床科学家发展奖的支持，以便在 Kevin D. Cooper 博士（皮肤科）的指导下获得单核细胞生物学的新专业知识。 CWRU的研究环境、资源和职业发展机会都是一流的，CWRU医学院最近被列为全美十大研究机构之一，皮肤科被列为美国NIH资助的顶尖项目。 候选人的近期目标是将拟议工作中的动物模型开发成可用于测试硬皮病干预措施的工具；长期目标是作为独立资助的研究人员在杰出的研究环境中发展皮肤单核细胞生物学和自身免疫性疾病基因转移的科学。 该提案涉及系统性硬化症/硬皮病的研究，这是一种病因不明的慢性自身免疫性疾病，其特征是体液和细胞介导的免疫改变，以及内脏和皮肤中胶原蛋白过度沉积，这被认为是由产生 TGFbeta 的活化单核细胞驱动的。 我们已经描述了一种非常有前途的硬皮病小鼠模型，它概括了硬皮病的许多重要特征。假设：单核细胞是 Scl GVHD 中的关键效应细胞。 TGF-β1 是一种主要的纤维化细胞因子，可导致 Scl GVHD 小鼠皮肤纤维化； TGF-β2 和 TGF-β3 在这种皮肤纤维化中起的作用即使有，也是次要的。皮肤纤维化可通过以下因素抑制：1) TGF-β 抗体，2) 潜伏相关肽 (LAP)，一种天然存在的 TGF-β 拮抗剂。 具体目标 1：研究导致 Scl GVHD 动物皮肤纤维化的早期关键事件的机制和顺序，以更好地了解纤维化疾病的病理生理学并设计新的有针对性的干预措施。 建立单核细胞流入皮肤、纤维化 TGFβ 的产生以及 proalpha(I) 胶原蛋白 mRNA 合成上调的关键参数，为体内重点干预措施奠定了基础。具体目标 II：进一步表征 Scl GVHD 中抑制 TGFbeta1 的体内干预措施。 我们在初步实验中表明，TGF-β LAP 和 TGF-β 抗体可抑制 Scl GVHD 动物的皮肤纤维化。 这些观察结果的进一步表征与我们对基本单核细胞生物学的理解、动物模型和自身免疫性疾病硬皮病中TGFβ驱动的纤维化过程以及潜在的硬皮病和人类移植物抗宿主病的治疗具有高度相关性。

The candidate, Anita C. Gilliam, is a junior faculty member on tenure track in Dermatology at Case Western Reserve University (CWRU), where she is developing a research career in molecular mechanisms of autoimmune disease. The proposed work draws on her experience in molecular biology and cutaneous immunobiology, and requests support for a mentored Clinical Scientist Development Award to acquire new expertise in monocyte biology under the mentorship of Dr. Kevin D. Cooper (Dermatology). The research environment, resources, and opportunities for career development at CWRU are superb, with CWRU School of Medicine recently listed as one of the top 10 research institutions in the country, and the Department of Dermatology as the top US program in NIH funding. The candidate's immediate goals are to develop the animal model in the proposed work into a vehicle useful for testing of interventions in scleroderma; long term goals are to develop the science of cutaneous monocyte biology and gene transfer in autoimmune disease as an independently funded investigator in an outstanding research environment. The proposal involves the study of systemic sclerosis/scleroderma, a chronic autoimmune disease of unknown etiology characterized by altered humoral and cell-mediated immunity, and excessive deposition of collagen in viscerae and skin, which is thought to be driven by activated monocytes making TGFbeta. We have characterized a very promising murine model for scleroderma that recapitulates many important features of scleroderma. Hypothesis: Monocytes are critical effector cells in Scl GVHD. TGF -beta1 is a major fibrogenic cytokine driving skin fibrosis in mice with Scl GVHD; TGF-beta2 and TGF-beta3 play minor if any roles in this cutaneous fibrosis. Skin fibrosis can be inhibited by: 1) antibodies to TGF-beta, 2), and latency associated peptide (LAP), a naturally occurring antagonist for TGF-beta. Specific Aim 1: To investigate the mechanism and sequence of early critical events leading to skin fibrosis in animals with Scl GVHD to better understand the pathophysiology of fibrosing disease and to devise novel focused interventions. Establishing the critical parameters of monocyte influx into skin, production of fibrogenic TGFbeta, and upregulation of proalpha(I) collagen mRNA synthesis provides a foundation for in vivo focused interventions. Specific Aim II: To further characterize in vivo interventions that inhibit TGFbeta1 in Scl GVHD. We have shown in preliminary experiments that TGF-beta LAP and antibodies to TGF-beta inhibit skin fibrosis in animals with Scl GVHD. Further characterization of these observations have high relevance to our understanding of basic monocyte biology, to the TGFbeta-driven fibrosing process in the animal model and in the autoimmune disease scleroderma, and potentially to the treatment of scleroderma and human graft versus host disease.