This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project attempts to combine emerging technology to develop the novel concept that """"""""tumor suppressor genes"""""""" (TSGs) form a functionally interactive network that - operating within neuronal and glial subsets of the hypothalamus - provide the system-wide control underlying the pubertal activation of LHRH secretion.
The aims are to: 1) construct a fist-stage architectural model of the TSG genetic network, and identify the cellular sites of expression of both upper echelon genes and genes situated at nodal points in the network. To achieve the first part of the aim we will test novel computational methods not yet applied to the dissection of complex biological processes in mammals;the second part will be accomplished using immunohistochemistry-in situ hybridization procedures;and 2) experimentally test the viability of the TSG network via perturbation of in silico predicted key components of the system. We propose to achieve this by disrupting TSG expression using the technology of small-interfering RNAs (siRNA) delivered to the hypothalamus via the novel approach of modified lentiviruses carrying dual siRNA transcriptional cassettes. Although siRNAs are widely used to perturb gene expression in mammalian cells, the methodology to achieve long-term silencing effects in vivo is still in its infancy.
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