CD24 Polymorphism and Acetaminophen Toxicity

描述（由申请人提供）：个体化药物反应和毒性挑战领域主题：04-GM-101 A。众所周知，药物的毒性因人而异。虽然已经确定了一些遗传位点，但大多数遗传因素仍然难以捉摸。到目前为止，已确定的遗传因素涉及药物代谢或对靶细胞的直接毒性。最近，我们发现CD24-Siglec10/G相互作用是宿主对对乙酰氨基酚诱导的坏死反应的关键调节因子。[印刷前][PMID: 19264983])在西方，这种药物与大多数药物过量引起的住院有关。基于我们对CD24与人类多种自身免疫性疾病相关的广泛研究(PNAS 100(25):15041-6；PLOS Genetics， 2007年4月6日；3(4):e49)，我们建议通过比较敲入人类CD24两个等位基因的小鼠对乙酰氨基酚的抗性，来测试唯一已知的编码CD24多态性是否会影响宿主对乙酰氨基酚的反应。此外，我们将建立一个遗传模型，以确定CD24传递的耐药性是否由于其调节造血细胞（特别是树突状细胞）产生炎症细胞因子，无论是使用CD24基因的谱系特异性缺失，骨髓嵌合体的产生，还是在CD11c+细胞上仅表达CD24的转基因小鼠。我们提出的研究可能潜在地确定个体化耐药性的重要遗传标记，并阐明CD24调节药物毒性的细胞机制。该提案响应04-GM-101*，个性化药物反应和毒性。拟议的研究将由两名新的博士后研究人员和一名技术人员进行。课程可于两年内完成。

DESCRIPTION (provided by applicant): Challenge Area of Personalized Drug Response and Toxicity Challenge Topic: 04-GM-101 A. Specific aims It is well established that drug toxicity varied individually. Although some genetic loci have been identified, most of the genetic factors remain to be elusive. Until now, the genetic factors identified are involved in either drug metabolism or in direct toxicity to the target cells. More recently, we identified CD24-Siglec10/G interaction as a key regulator for host response to necrosis induced by acetaminophen, which is (Science. 2009 Mar 5. [Epub ahead of print]PMID: 19264983)the drug that is associated with the most of the drug overdose-induced hospitalization in the West. Based on our extensive studies on CD24 association with multiple autoimmune disease in humans (PNAS 100(25):15041-6; PLOS Genetics, 2007 Apr 6;3(4):e49), we propose here to test if the only known coding CD24 polymorphism would affect host response to acetaminophen by comparing mice with knockin of the two alleles of human CD24 for their resistance to the acetaminophen. In addition, we will develop a genetic model to determine whether the drug resistancy conveyed by CD24 is due to its regulation of production of inflammatory cytokine by hematopoietic cells, especially dendritic cells, either using a lineage-specific deletion of the CD24 gene, generation of bone marrow chimera or transgenic mice expressing CD24 exclusively on CD11c+ cells. Our proposed studies may potentially identify an important genetic marker for personalized drug resistance and elucidate cellular mechanism by which CD24 regulates drug toxicity. This proposal responds to 04-GM-101*, personalized drug response and toxicity. The proposed studies will be carried out by two new postdoctoral researchers and a technician. The studies can be completed within 2 years. PUBLIC HEALTH RELEVANCE: It is well established that drug toxicity varied individually. We recently identified CD24-Siglec10/G interaction as a key regulator for host response to liver necrosis induced by acetaminophen (Science. 323:1722 2009). Previous research has estimated that there are 60,000 cases of acetaminophen overdose annually, most of which are suicide attempts. Nearly 26,000 are hospitalized each year. Based on our extensive studies on CD24 association with multiple autoimmune disease in humans (PNAS 100:15041, 2003; PLoS Genetics 3:e49, 2007), we propose here to test if the only known coding CD24 polymorphism would affect host response to acetaminophen. We will compare mice with knockin of the two alleles of human CD24 for their resistance to the acetaminophen. We will develop a genetic model to determine whether the drug resistance conveyed by CD24 is due to its regulation of production of inflammatory cytokine by dendritic cells. Our proposed studies may potentially identify an important genetic marker for personalized drug resistance and elucidate cellular mechanism by which CD24 regulates drug toxicity. This proposal responds to 04-GM-101*, personalized drug response and toxicity.