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Study of the molecular mechanisms regulating the kinase IKK complex by proinflammatory cytokines IL-1beta and TNF-alpha in pancreatic beta cells and their role in induction of transcription factor NF-kB

Grant number: 11/03976-3
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): August 01, 2011
Effective date (End): July 31, 2013
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Valor Concedido/Desembolsado (R$): 43,204.32 / 43,204.32
Principal Investigator:Antonio Carlos Boschiero
Grantee:Keli Cristina Benedicto
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Type 1 diabetes (T1D) is characterized by a selective destruction of insulin producing pancreatic beta cells, by the immune system. During the autoimmune assault, pro-inflammatory cytokines, such as interleukin (IL)-1b, tumour necrosis factor (TNF)-a and interferon (IFN)-g contribute for beta cells death, manly via NF-kB activation. Since NF-kB is a key regulator of several cellular responses to different factors and has preferentially anti-apoptotic effect in other cell types, it is of great interest to better understand the specific characteristics that lead to its pro-apoptotic effect in beta cells. Thus, specific interventions could be used to prevent beta cell destruction after an auto-immune assault, with preserved cellular homeostasis. Induction of NF-kB activation by pro-inflammatory cytokine differs from other cell types by intensity and duration, in additon, IL-1b induces higher NF-kB activation, leading to differential expression of genes putatively involved in beta cell dysfunction and death, compared to TNF-a. This effect seems to be related to a higher intensity (induced by IL-1b) of kinases that modulate NF-kB activation, such as IKK (a convergence point for extracellular signalling in NF-kB activation). Recently, we observed that IL-1b also induces degradation of one of the three IKK subunits (IKKb), which is not observed in TNF-a treatment. In this project we intent to clarify the specific molecular characteristics involved in the activation and usage of the IKKs subunits (a, b and g) for NF-kB activation by IL-1b and TNF-a. To this end, we are going to use siRNAs for silencing of specific kinases and adaptor proteins involved in the activation signalling cascade of IKK complex in insulin producing cell lines and islet dispersed cells from rat and mouse. The effects of this silence will be analyzed in the viability and function of the beta cells. The most relevant results will be confirmed in rat and mouse islets, to evaluate the impact of these findings in a more complex environment. The results obtained in the present study could provide important information for the developmente o new methodology in the genetic intervention to prevent beta cell destruction during T1D. (AU)

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