CD24 Polymorphism and Acetaminophen Toxicity

描述（由申请人提供）：个性化药物反应和毒性挑战主题的挑战区域：04-GM-101 A。具体目标众所周知，药物毒性因个体而异。虽然一些遗传位点已被确定，但大多数遗传因素仍然是难以捉摸的。到目前为止，已确定的遗传因素参与药物代谢或对靶细胞的直接毒性。最近，我们鉴定了CD 24-Siglec 10/G相互作用作为宿主对由对乙酰氨基酚诱导的坏死的应答的关键调节剂，这是（Science. 2009年3月5日[Epub PMID：19264983），该药物与西方大多数药物过量导致的住院治疗有关。基于我们对CD 24与人类多种自身免疫性疾病相关性的广泛研究（PNAS 100（25）：15041-6; PLOS Genetics，2007年4月6日;3（4）：e49），我们在此建议通过比较敲入人CD 24的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CD 24多态性是否会影响宿主对乙酰氨基酚的反应。此外，我们将开发一个遗传模型，以确定是否由CD 24传递的耐药性是由于其调节造血细胞，特别是树突状细胞的炎症细胞因子的产生，无论是使用一个谱系特异性缺失的CD 24基因，骨髓嵌合体或转基因小鼠表达CD 24只在CD 11 c+细胞。我们提出的研究可能会发现一个重要的遗传标记的个性化耐药和阐明细胞机制，CD 24调节药物毒性。本提案响应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。这些研究可以在两年内完成。 公共卫生相关性：众所周知，药物毒性因个体而异。我们最近鉴定了CD 24-Siglec 10/G相互作用作为宿主对由对乙酰氨基酚诱导的肝坏死的应答的关键调节剂（Science. 323：1722 2009）。此前的研究估计，每年有60，000例对乙酰氨基酚过量服用的病例，其中大部分是自杀未遂。每年有近26，000人住院。基于我们对CD 24与人类多种自身免疫性疾病相关性的广泛研究（PNAS 100：15041，2003; PLoS Genetics 3：e49，2007），我们建议在此测试唯一已知的编码CD 24多态性是否会影响宿主对对乙酰氨基酚的反应。我们将比较敲入人类CD 24两个等位基因的小鼠对醋氨酚的抗性。我们将建立一个遗传模型来确定CD 24所传递的耐药性是否是由于其调节树突状细胞产生炎性细胞因子所致。我们提出的研究可能会发现一个重要的遗传标记的个性化耐药和阐明细胞机制，CD 24调节药物毒性。本提案响应04-GM-101*，个性化药物反应和毒性。

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.