No abstract

Morphine is a widely used analgesic, but its use in clinical precision medicine is limited by the variance in response among individuals. Although previous studies have shown that individual differences in morphine can be explained in terms of pharmacodynamics and pharmacokinetics, genetic polymorphisms also play an important role. However, the genetic basis of different sensitivity and tolerance susceptibility to morphine remains ambiguous. Using 15 strains of inbred Genetic Diversity (GD) mice, a new resource with wide genetic and phenotypic variation, we demonstrated great variance in sensitivity to morphine analgesia and susceptibility to morphine tolerance between different GD strains. Among-individual variance in response to morphine analgesia in the population can be modeled in GD mice. Two loci respectively may be associated with the among-individual variance in morphine sensitivity and tolerance, confirming the role of genetic factors in among-individual different responses to morphine. These results indicate that GD mice may be a potential tool for the identification of new biomarkers to improve the clinical administration of morphine.

Background Busulfan (BU) is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell (HSC) transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells. The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU. Different susceptibilities were demonstrated in genetically diverse (GD) mice in our preliminary research. Methods Three strains of GD mice with different susceptibilities to BU‐induced HSC injury were used for screening biological markers of HSC injury susceptibility in urine. The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins. Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme‐linked immunoassay (ELISA). Results Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence, apoptosis, and angiogenesis; whereas the differential proteins of the high‐susceptible strain were enriched for the regulation of bone marrow microenvironment pathways, those of low‐susceptible strain were enriched for the proapoptotic effect of GTPase pathways. Based on protein abundance differences, several urinary proteins that may be indicative of susceptibility were screened, and ELISA validation results showed that angiotensin‐converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning. Conclusions This study indicates that urinary protein levels can reflect differences in susceptibility to BU‐induced HSC injury. Using GD mice to construct genetic difference models will provide preclinical data for screening BU‐related biological markers.