| Grant number: | 11/12297-2 |
| Support Opportunities: | Regular Research Grants |
| Start date: | April 01, 2012 |
| End date: | September 30, 2014 |
| Field of knowledge: | Health Sciences - Medicine - Medical Clinics |
| Principal Investigator: | Sabri Saeed Mohammed Ahmed Al-Sanabani |
| Grantee: | Sabri Saeed Mohammed Ahmed Al-Sanabani |
| Host Institution: | Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
| Associated researchers: | Ester Cerdeira Sabino |
Abstract
The HTLV-1 was the first human retrovirus to be isolated and has been shown to cause a broad spectrum of clinical manifestations including adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraperesis (HAM/TSP). The latency period to induce ATLL can be extremely long (30 to 50 years), indicating that combination/cooperation of specific genetic and viral events are involved in the multi-step evolution of silent infection to full-blown ATLL. The mechanisms responsible of cells transformation to ATLL are not yet fully understood. It is believed that continual viral expression of HTLV proteins, particularly tax, and the abundant proliferation of lymphocytes may increase the probability of inflammation and stimulate cell migration, thus increase the risk of HAM/TSP and other HTLV-1-associated inflammatory diseases. Also, enhanced lymphocyte proliferations would increase the chance of acquiring mutations that could increase the risk of malignant transformation and the development of ATLL. In recent years, in vivo study reveals interesting findings that demonstrate an absence of tax expression in approximately 60% of late leukemia's. These intriguing results raise an important question, what are other factor(s) needed to maintain the leukemic phenotype of ATL cells in the absence of tax? One possible answer for this question might lie in deregulation of cellular miRNAs in ATL transformed cells that permanently changes the cellular regulation of gene expression patterns and maintaining the malignant phenotype independently of tax protein. In this regard, few studies have demonstrated that cells infected with HTLV-1 have different expression levels of human miRNAs, suggesting that tax is responsible for cell transformation and miRNAs for the permanence of the transformed cells. Moreover, these studies also point to the rex gene as a possible attenuator of intracellular antiviral response, acting as a silencer of miRNAs. Against this background, it appeared that measuring miRNAs abundances provides more comprehensive information about the molecules most closely involved in cellular regulation and operation. In this study, we aim to evaluate the expression levels of all human miRNAs in T-cells from HTLV-I asymptomatic carriers, patients with ATLL and patients with HAM/TSP. Our approach to identify potential miRNAs and/or isoforms molecules involves utilizing high throughput sequencing to determine the quantitative analysis of each miRNAs in each group. A comparative analysis of these molecules in each of these diseased and non-diseased states should yield valuable insight into identifying miRNAs and/or isoforms involved with the pathogenesis of both ATLL and HAM/TSP. We also aim to make use of the deep sequencing technology to underscore the importance of assessing t-cell clonality and their association with HTLV-1 proviral load. Deep sequencing of t-cell receptor is potentially useful in tracking monoclonal T cell expansions and enables detection of clonal T cell populations that do not show aberrant cell surface marker. This high-resolution analysis will offers the potential for predicting patients predisposed to ATLL or HAM/TSP. Overall, the results are expected to yield novel data for understanding the ATLL and HAM/TSP disorders associated with HTLV-1 infection. In addition, the novel candidate miRNA that we identify using these sequencing techniques may yield potentially valuable therapeutic targets for HTLV-1 disorders. This approach will allow us to identify potential biomarkers in each clinical entity, search for new miRNAs and/ or isoforms, examine the expression of mRNA for the HTLV- I tax/rex, determine the rate of t cell clonality and their association with HTLV-1 proviral load. (AU)
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