Role of the natural CXCR4 antagonist ALB408-423 in health and disease

天然 CXCR4 拮抗剂 ALB408-423 在健康和疾病中的作用

• 批准号: 234896551
• 负责人: Professor Dr. Jan Münch
• 金额: --
• 依托单位: Institut für Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234896551?language=en
• 关键词: Role; natural; CXCR4; antagonist; ALB408

The CXCR4/CXCL12 signaling pair plays an essential role in homeostasis and, if deregulated, it is associated with a variety of pathophysiological conditions like metastasis or chronic inflammatory processes. Furthermore, the G protein-coupled receptor (GPCR) CXCR4 serves as cofactor for HIV-1 entry. In human blood, we identified a fragment of serum albumin, ALB408-423, that dose-dependently blocks CXCR4- but not CCR5-tropic HIV-1 infection. We provide evidence that ALB408-423 competes with binding of CXCL12 to CXCR4 thereby blocking signaling via the receptor. ALB408-423 inhibits CXCL12-induced calcium mobilization, receptor internalization and tumour cell migration. Importantly, a single administration of ALB408-423 induced stem cell mobilization in mice, demonstrating its in vivo activity. In sum, ALB408-423 is an endogenous antagonist of CXCR4 and likely represents an as-yet-unknown key regulator of CXCR4 function. Therefore, I propose a research project that aims to determine the role of ALB408-423 in health and disease. Within this proposal we aim at 1) establishing means to easily quantify ALB408-423 in body fluids and other specimens; 2) clarifying its role in HIV-1 pathogenicity and transmission; 3) investigating its generation from the precursor albumin; 4) studying whether CXCR4 antagonism by ALB408-423 is a conserved mechanism in mammals; and finally 5) generating optimized ALB-based CXCR4 antagonists for the treatment of CXCR4-linked diseases or the mobilization of stem cells. The work proposed herein will provide fundamental new insights into the regulation of the pivotal CXCR4 receptor and might pave the way for a better understanding of AIDS pathogenesis or the development of new therapeutic strategies for CXCR4-linked diseases.

CXCR 4/CXCL 12信号传导对在体内平衡中起重要作用，并且如果失调，则其与多种病理生理状况如转移或慢性炎症过程相关。此外，G蛋白偶联受体（GPCR）CXCR 4作为HIV-1进入的辅因子。在人类血液中，我们鉴定了血清白蛋白的片段ALB 408 -423，其剂量依赖性地阻断嗜CXCR 4但不阻断嗜CCR 5的HIV-1感染。我们提供的证据表明，ALB 408 -423与CXCL 12竞争结合CXCR 4，从而阻断通过受体的信号传导。ALB 408 -423抑制CXCL 12诱导的钙动员、受体内化和肿瘤细胞迁移。重要的是，单次给予ALB 408 -423诱导小鼠中的干细胞动员，证明了其体内活性。总之，ALB 408 -423是CXCR 4的内源性拮抗剂，可能是CXCR 4功能的一种未知的关键调节因子。因此，我提出了一个研究项目，旨在确定ALB 408 -423在健康和疾病中的作用。在这一提议中，我们的目标是：1）建立易于定量体液和其他标本中ALB 408 -423的方法; 2）阐明其在HIV-1致病性和传播中的作用; 3）研究其从前体白蛋白中的产生; 4）研究ALB 408 -423对CXCR 4的拮抗作用是否是哺乳动物中的保守机制;最后5）产生优化的基于ALB的CXCR 4拮抗剂，用于治疗CXCR 4相关疾病或动员干细胞。本文提出的工作将为关键CXCR 4受体的调控提供基本的新见解，并可能为更好地理解艾滋病发病机制或开发CXCR 4相关疾病的新治疗策略铺平道路。