NF-kB Promoter-Recruitment in dendritic cell differentiation - possible modulation by tumour cells

• Grant number: 14/14302-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: November 01, 2014
• End date: October 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Ana Carolina Franco Ferreira
• Supervisor: Simona Saccani
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), France
• Associated to the scholarship: 12/17643-9 - DENDRITIC CELLS FUNCTION DISABILITY PROMOTED BY CANCER MIGHT BEGIN AT THEIR HEMATOPOIETIC PRECURSORS, BP.PD

Abstract

The tumour effect on dendritic cells (DCs) is an important mechanism of tumour evasion, since functional modification of DCs can promote serious consequences on the immune response. However, the cellular mechanisms involved in DCs' functional changes in cancer are poorly known. Consequently, for the achievement of desired results when using DCs on cancer treatments it becomes crucial to understand the mechanisms responsible for these changes. In this context, knowing that changes in gene expression are involved in DC maturation, studies that seek deeper knowledge of signal transduction and gene regulation in these cells are of great relevance. These mechanisms are poorly characterized, especially in pathological situations such as cancer. Thus, the family of nuclear factor kappa-B (NF-kB) is a fundamental target of research, since it is involved in DCs differentiation/maturation and its misregulation is associated with the cancer development. Previous results showed that the co-culture with breast cancer cell lineages induces changes in the NF-kB expression level and cellular localization, in monocytic cells (THP-1). Besides, it affects the NF-kB activation induced by DC differentiation/maturation stimuli and the effect differs among NF-kB subunits. Knowing that the composition of active NF-kB dimers is an important - but unclear - mechanism of transcription control, the study of the role of the subunits in the modulation promoted by tumour cells and on how this disbalance impairs DC differentiation, is extremely relevant and promising. Thus, the aim of this proposal is to analyse the modulation promoted by tumour cells on NF-kB pathway in monocytic cells and its effects on transcription control related do DC differentiation/maturation, focusing on NF-kB dimer specificity. For that, we intend to characterize the genome-wide occupancy pattern of NF-kB in our experimental conditions and also in a dimer-specific manner. Besides, we intend to use genetic engineering techniques to try to prevent/reverse the alterations observed. (AU)