Challenge Area of Personalized Drug Response and Toxicity Challenge Topic: 04-GM-101 A.
Specific aims I t 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.
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.
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