Analysis of Regulatory and Interaction Networks from Clusters of Co-expressed Genes - Clustering Challenges in Biological Network - page 75

3.4. Intervention Strategies
The idea of inhibiting multiple targets by exploring the properties of networks of
interacting proteins is gaining an ever-increasing popularity [78]. Network toler-
ance in the presence of attacks, i.e., elimination of nodes, proves to be a promising
and constructive way of determining putative intervention targets. Of particular
importance is the realization that the same structural effects can be the result of
not only a single node (hub) elimination which can be detrimental, but also the
result of the simultaneous elimination of multiple interactions [61] with the de-
sired structural effects yet not the lethal consequences. In fact, this is the principle
behind the essential action of many multi-target drugs such as non-steroidal anti-
inflammatory drugs (NSAIDs). Selecting, therefore, tentative targets for interfer-
ence or elimination can be rationalized from the point of view of the resulting
network interactions. Even though the importance of major hubs has been es-
tablished in terms of the lethal consequences of eliminating such nodes [43] true
opportunities lie in the potential for the concurrent (partial) elimination of inter-
actions of multiple carefully selected targets.
The in silico approaches proposed in this paper, analyze interaction networks
by exploring the topology of the interactions of sub-sets of maximally informa-
tive genes. Multiple approaches have been proposed for interfering with gene
products in the context of altering cellular responses. Identifying a regulatory
layer and the core nodes of that layer provides a mechanism to elucidate inter-
vention points to attenuate the inflammatory process. Intervention utilizing these
TF proteins could theoretically take one of three forms: 1) inhibition of TF pro-
duction using knockout or silencing techniques; 2) blocking TF activity through
competitive inhibition; 3) blocking TF activity through suicide inhibition. Current
approaches for silencing focus on the use of siRNA techniques [88]. In this ap-
proach double-stranded RNA (dsRNA) is digested by the dsRNA-specific RNase
III enzyme dicer into small interfering RNAs (siRNAs). The siRNAs then assem-
ble with a multiprotein nuclease complex, RNA-induced silencing complex [89],
which unwinds the dsRNAs and degrades target mRNAs homologous to the sin-
gle stranded siRNA in a sequence-specific manner. The result of this process is
the degradation of mRNA needed as a template for protein production, thereby
inhibiting the production process, and depleting pools of proteins needed for spe-
cific enzymatic reactions. One specific example of siRNA utilized for intervention
in inflammatory response is the application of siRNA techniques to inhibition the
production of STAT-3 in order to elucidate key signaling molecules in the inflam-
matory response pathway [90]. A future application of this work would be to
utilize the ability to block STAT-3 production to actually modulate the inflamma-