Over all objective of this study is to understand the molecular mechanisms and gender differences in response of male and female human umbilical vein endothelial cells (HUVEC) to stress, with emphasis on cross talk between PI-3 Kinase/Akt and p38 MAP Kinase pathways. It is found that male fetus has greater mortality rate than female. The molecular basis of the observed gender difference in mortality of male and female fetus is poorly understood. Phosphatidylinositol 3-kinase (PI-3 Kinase)/ Akt pathway is the key controller of endothelial cell viability determining endothelial cell viability. Withdrawal of growth factor or exposure to cytokines inhibits PI-3 Kinase /Akt signaling in endothelial cells and induces apoptosis. Decline of PI-3 Kinase/Akt induces an upregulation of stress induced p38 MAP Kinase. The cross-talk between mitogen -activated protein kinase (MAP Kinase) and PI-3 Kinase/Akt pathway and the role of activated p38 MAP Kinase in apoptosis is poorly understood. In this novel proposal we link the viability of fetus to the functional integrity and survival of HUVEC which is maintained by PI-3 Kinase /Akt signaling. Although there is lack of textual data, we have included preliminary data where male HUVEC is more susceptible than female to wortmannin (an inhibitor of PI-3 Kinase) induced stress, leading to sharper decline in pAkt and dramatic onset of apoptosis. We will consolidate this preliminary finding by assessing the susceptibilities of male and female HUVECs to a variety of stress. This proposal will also determine whether gender difference in susceptibility of male and female HUVEC to stress is regulated by p38 MAP Kinase. SB 203580 (a specific inhibitor of p38 MAP Kinase) or small-inhibitory RNA (si-RNA) against p38 MAP Kinase will be used to inhibit p38 MAP Kinase activity. Overexpression of MKK6, an upstream kinase of p38 MAP Kinase will also be utilized to elucidate the potential cross-talk between p38 MAP Kinase and PI-3 Kinase/ Akt pathway. Apoptosis induction will be determined by TUNEL assay, Annexin V staining and caspase-3 and -9 activities. We will also examine whether 17-?-estradiol (E2) modulates the cross talk between p38 MAP Kinase and PI-3 Kinase /Akt signaling in male and female HUVEC. Human umbilical vein endothelial cells from male and female umbilical cord will be used to study the gender difference in the response to stress induced apoptosis. This investigation could help us understand the mechanisms by which the mortality rate of male fetus and neonates is higher than female. ? ? ?
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