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Inves0000000000000tigation of the utility of the TAT protein transduction domain for in Vivo siRNA delivery

Reference	BB/C508234/1
Principal Investigator / Supervisor	Professor Mark Lindsay
Co-Investigators / Co-Supervisors	Professor Maria Belvisi
Institution	Imperial College London
Department	Dept of Medicine
Funding type	Research
Value (£)	249,308
Status	Completed
Type	Research Grant
Start date	10/01/2005
End date	09/01/2008
Duration	36 months

Abstract

The recent advent of small interference RNA (siRNA) has revolutionised functional genomics by providing a relatively rapid and inexpensive means to identify the role of genes through the attenuation of mRNA expression. However, the application of siRNA is normally limited by the availability of effective and non-toxic mechanisms for their delivery into cells/tissues. These problems can be largely overcome in vitro using a variety of technologies including polycationic lipids/polymers, viral delivery, electroporation and microinjection. In contrast, few strategies presently exist for in vivo delivery which will be central to the ultimate scientific and therapeutic application of this emerging technology. Interestingly, a number of recent publications have demonstrated the use of a short cationic peptide sequences derived from the HIV TAT transcription protein (TAT), for the in vivo and non-toxic delivery of biological active peptides and proteins in mouse models. The aim of this project is to extend these studies and assess the utility of TAT for in vitro and in vivo siRNA delivery. Using p38 MAP kinase as the target for siRNA knockdown, initial studies will identify effective sequences and optimise the TAT mediated delivery in mouse cell lines. In order to determine cells or tissues that might be amenable to this technique, TAT mediated delivery of labelled siRNA (tissue distribution and pharmacokinetics) will be examined following intraperitoneally and intravenous administration into mice. Importantly, parallel studies will also be undertaken to measure TAT mediated siRNA delivery and subsequent p38 MAP kinase mRNA and protein knockdown in brain, lung, skin, liver, kidney, blood, heart, muscle, small intestines, stomach and thymus. Finally since p38 MAP kinase activation has been demonstrated to be central to the mechanism of TNFa release following intraperitoneal LPS administration and the induction of systemic inflammation, will assess whether this response can be attenuated by TAT-siRNA following.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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