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Molecular mechanisms of MA anticancer activity in vitro
Maternins are naturally occurring proteolitic fragments from the b-chain of human chorionic gonadotropin (b-hCG). Maternin-a (MAa) is composed by aa 55-89 and MAb is aa 41-54 of bhCG. Both peptides suppress tumor growth in vivo and in vitro. Preliminary results, obtained in my laboratory, indicate a direct effect on caspase activation, leading to cell cycle arrest and apoptosis. F. Romerio will describe the molecular mechanisms in detail.
As outlined in our recently submitted program project, we will test the hypothesis that MAa and MAb promote cell death and alter cell cycle regulation in vitro and in vivo by inducing activation of caspase-8 and caspase-3, and followed by reduced function of the MEK/ERK pathway.
Molecular mechanisms of Tat-mediated immuno-suppression
It has been demonstrated in vitro that Tat is secreted by acutely infected CD4+ T cells and that extracellular Tat can then dysregulate CD4+ T cell function. We have previously demonstrated that extracellular Tat mediates the increase of CXCR4 and the hyper-activation of CD4+ T-cells. We unveiled the molecular mechanisms responsible for hyperactivation of CD4+ T cells. Both of these effects lead to increased susceptibility to HIV infection.
When taken-up by uninfected cells, extracellular Tat also promotes IFN-a expression in monocyte-derived macrophages. Overexpression of IFN-a may contribute to immune-disfunction observed in HIV-seropositive subjects by reducing proliferation of CD4+ T-cells. F. Romerio will describe more in detail the mechanism responsible for the anti-proliferative effect of IFN-a on CD4+ T-cells.
HHV-6 and MS
Multiple Sclerosis (MS) is a common demyelinating disorder of the central nervous system (CNS) with varied clinical manifestations. A possible role of Human Herpes Virus (HHV)-6A in MS pathogenesis has been recently proposed. On the basis of restriction analysis, in vitro tropism studies, and antigenic properties, HHV-6 can be separated into two variants, designated variant A and variant B. However, in order to better establish a causative, or contributing, role of HHV-6 in MS, it is necessary to improve the diagnostic assays.
Currently, there are currently no rapid serological methods to distinguish between HHV-6A and B. Consequently, discrimination between the two viruses relies on cumbersome methods like PCR followed by restriction enzyme digestion. In addition, the epitopes, that could distinguish the two virus subtypes are unknown. The broad objective of this project is to understand the possible role of HHV-6 in Multiple Sclerosis (MS). Our central hypothesis is that HHV-6A is a contributing factor of MS. We propose that HHV-6A infection and/or reactivation accounts for some of the clinical manifestations in MS patients. We also propose to determine the immuno-dominant epitopes expressed by this subtype, which eventually could be the basis for immunizing strategies against HHV-6A.
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