Modeling of miRNA and Drug Action in the EGFR Signaling Pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer

Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations

ENHANCEMENT OF HEPATIC-ARTERY RESISTANCE TO BLOOD-FLOW IN PREECLAMPSIA IN PRESENCE OR ABSENCE OF HELLP-SYNDROME (HEMOLYSIS, ELEVATED LIVER-ENZYMES, AND LOW PLATELETS)

OBJECTIVE: Our purpose was to test the hypothesis that the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is the result of excessive vasoconstriction of the hepatic arterial circulation. STUDY DESIGN: Doppler ultrasonography was used to measure the pulsatility index of the common hepatic artery in 14 women with preeclampsia, 15 with preeclampsia complicated by HELLP syndrome, and 8 with HELLP syndrome but without proteinuria. Gestational age ranged from 24 to 38 weeks. The study group was compared with a reference group (n = 42). RESULTS: Both in preeclampsia and in the HELLP syndrome the hepatic artery pulsatility index values were significantly increased compared with the reference group. However, no significant differences were found between the preeclamptic group, the HELLP group with proteinuria, and those with HELLP without proteinuria. CONCLUSIONS: These findings indicate that hepatic artery resistance to blood flow is increased in preeclampsia in the presence or absence of the HELLP syndrome. The results also demonstrate that vasoconstriction of the hepatic arteries is not more pronounced in the HELLP syndrome than in other manifestations of preeclampsia. Therefore factors other than vasoconstriction are likely to be responsible for the development of the HELLP syndrome