CHARACTERIZATION OF FRACTALKINE IN VITRO AND IN VIVO

分形因子的体外和体内表征

• 批准号: 6605662
• 负责人: LILI FENG
• 金额: $ 21.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605662
• 关键词: biological signal transduction; cell adhesion; cell proliferation; chemokine; chemotaxis; inflammation; laboratory rabbit; laboratory rat; ligands; macrophage; mucins; neutralizing antibody; protein structure function; renal glomerulus

DESCRIPTION (Adapted from Investigator's Abstract): Fractalkine, a newly cloned CX3C chemokine, is an endothelium-derived lymphoctye and macrophage chemoattractant, and is unique as the only chemokine mounted on a mucin stalk and having a transmembrane domain. This structure may optimize its function in high-flow vascular circuits such as the renal glomerulus. The Principal Investigator has shown that a neutralizing antibody (Ab) against the receptor for fractalkine, CX3CR1, almost completely prevented CD8+ lymphocyte-dependent and monocyte/macrophage-related anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) in the Wistar-Kyoto (WKY) rat. This suggests that the fractalkine/CX3CR1 ligand/receptor pair play a central role in immune-mediated inflammation in the glomerulus. The Principal Investigator proposes to explore the mechanisms of fractalkine regulation and signaling in glomerular endothelial cells (GenC), as well as how fractalkine-expressing GenC cross-communicate with CX3CR1-bearing cells, mainly monocytes/macrophages. The Principal Investigator will study when fractalkine can be induced, what fractalkine can regulate, and how fractalkine can function. The Principal Investigator will, by dissecting the individual domains of fractalkine (including its chemokine, mucin, transmembrane, and cytoplasmic domains), study the role of the molecule in fractalkine-mediated cellular events, including chemotaxis, cell adhesion, activation of macrophage proliferation in vitro in GenC and in vivo in renal inflammation. The Principal Investigator will continue to develop a fractalkine antagonist for better in-depth understanding of the relationship between the structure and activity of the molecule, which in addition will provide insightful information for drug design. Finally, the Principal Investigator will use the antagonist, along with other chemokine antagonist controls and blockers, to determine the in vivo effects of fractalkine on acute inflammation and also on the proliferation of monocytes/macrophages as they contribute to continued injury and destruction in experimental glomerular and tubulointestinal renal injury. The Principal Investigator believes that these studies will provide new drug targets for many human disorders that may be fractalkine/CX3CR1-associated, including GN, vasculitis, allograft rejection, ischemia/reperfusion injury, thrombotic angiopathies, and atherosclerosis.

描述（改编自研究者摘要）：Fractalkine，一种新克隆的 CX3C 趋化因子，是一种内皮源性淋巴细胞和巨噬细胞 化学引诱剂，是唯一安装在粘蛋白茎上的趋化因子 并具有跨膜结构域。该结构可以优化其功能 高流量血管回路，例如肾小球。校长 研究人员表明，针对受体的中和抗体 (Ab) 对于 fractalkine，CX3CR1，几乎完全阻止 CD8+ 淋巴细胞依赖性 和单核细胞/巨噬细胞相关的抗肾小球基底膜（GBM） Wistar-Kyoto (WKY) 大鼠中 Ab 诱导的肾小球肾炎 (GN)。这表明 fractalkine/CX3CR1 配体/受体对在 肾小球免疫介导的炎症。首席研究员 提出探索 fractalkine 调节和信号传导的机制 肾小球内皮细胞 (GenC)，以及表达 fractalkine 的 GenC 与携带 CX3CR1 的细胞（主要是单核细胞/巨噬细胞）交叉通讯。这 首席研究员将研究什么时候可以诱导分形因子，什么 fractalkine 可以调节，以及 fractalkine 如何发挥作用。校长 研究人员将通过剖析 fractalkine 的各个域 （包括其趋化因子、粘蛋白、跨膜和细胞质结构域），研究 该分子在 fractalkine 介导的细胞事件中的作用，包括 趋化性、细胞粘附、体外巨噬细胞增殖激活 GenC 和体内肾脏炎症。首席研究员将 继续开发 fractalkine 拮抗剂以更好地深入了解 分子结构与活性之间的关系， 此外将为药物设计提供富有洞察力的信息。最后， 首席研究员将使用拮抗剂以及其他趋化因子 拮抗剂对照和阻断剂，以确定体内效果 fractalkine 对急性炎症和增殖的影响 单核细胞/巨噬细胞，因为它们有助于持续损伤和破坏 实验性肾小球和肾小管肾损伤。校长 研究人员相信这些研究将为许多药物提供新的靶点 可能与 fractalkine/CX3CR1 相关的人类疾病，包括 GN、 血管炎、同种异体移植排斥、缺血/再灌注损伤、血栓形成 血管病和动脉粥样硬化。

项目成果

Blocking of monocyte chemoattractant protein-1 during tubulointerstitial nephritis resulted in delayed neutrophil clearance.

肾小管间质性肾炎期间单核细胞趋化蛋白-1 的阻断导致中性粒细胞清除延迟。

• DOI: 10.1016/s0002-9440(10)62039-1
• 发表时间: 2005
• 期刊: The American journal of pathology
• 作者: Li,Ping;Garcia,GabrielaE;Xia,Yiyang;Wu,Wei;Gersch,Christine;Park,PyongWoo;Truong,Luan;Wilson,CurtisB;Johnson,Richard;Feng,Lili
• 通讯作者: Feng,Lili