INHIBITION OF MONOCYTE TGFB1-INDUCED SKIN FIBROSIS

抑制单核细胞 TGFB1 诱导的皮肤纤维化

• 批准号: 6374761
• 负责人: ANITA C GILLIAM
• 金额: $ 12.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-14 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374761
• 关键词: RNase protection assay; cellular immunity; flow cytometry; gene therapy; genetically modified animals; graft versus host disease; humoral immunity; in situ hybridization; laboratory mouse; migration inhibition factor; monocyte; pathologic process; scleroderma; sclerosis; transcription factor; transforming growth factors

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.

候选人Anita C. Gilliam是凯斯西储大学（CWRU）皮肤病学终身教职的初级教员，她正在发展自身免疫性疾病分子机制的研究事业。 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，并要求支持指导临床科学家发展奖，以在Kevin D.库珀（皮肤科）。 CWRU的研究环境，资源和职业发展机会非常好，CWRU医学院最近被列为全国十大研究机构之一，皮肤科系是NIH资助的美国顶级项目。 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者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，其特征在于体液和细胞介导的免疫力改变，以及内脏和皮肤中胶原蛋白的过度沉积，这被认为是由活化的单核细胞产生TGF β驱动的。 我们已经描述了一个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 -β 1是Scl GVHD小鼠中驱动皮肤纤维化的主要纤维化细胞因子; TGF-β 2和TGF-β 3在这种皮肤纤维化中起次要作用（如果有的话）。皮肤纤维化可以通过以下抑制：1）TGF-β的抗体，2）和潜伏相关肽（latency associated peptide，TGF-β的天然拮抗剂）。 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重点干预措施。 建立单核细胞流入皮肤、产生纤维化TGF β和上调前α（I）胶原mRNA合成的关键参数为体内集中干预提供了基础。具体目标II：进一步表征在Scl GVHD中抑制TGF β 1的体内干预。 我们已经在初步实验中表明，TGF-β抑制剂和TGF-β抗体抑制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础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TGF β驱动的纤维化过程以及硬皮病和人移植物抗宿主病的治疗具有高度相关性。