To date, the molecular mechanisms responsible for the remarkable genetic heterogeneity found in ADPKD cysts remain unknown. Similar karyotypic alterations have been described consequently to genomic instability. Our overall hypothesis is that PC1 disregulation contributes to the cystogenic hyperproliferative process by altering normal centrosomal functions and cell cycle progression, leading to genomic instability. Our preliminary results have uncovered strong evidence in support of this proposition. Specific siRNA- mediated inhibition of PC1 altered cell cycle progression and centrosome amplification in vitro, a finding corroborated in human ADPKD renal tissues. Loss of centrosome integrity was associated with dramatic genomic instability. The experimental focus of this application is to elucidate the molecular mechanisms underlying these novel findings. The first specific Aim is to determine whether PC1 disregulation causes an abnormal modulation of the proteins involved in the centrosome duplication process. The second specific Aim is to evaluate molecular mechanisms by which PC1 knockdown may cause interference with the normal cell division cycle progression. The third specific Aim is to characterize in vivo the role of PC1 knockdown in cystic hyperproliferation and centrosome amplification, using a transgenic mouse model containing a doxycyclin inducible siRNA specific for murine PKD1. Taken together, these novel studies will expand therapeutic cell cycle targets for drug development, as well as our understanding of the disease process.
The elucidation of mechanisms underlying ADPKD hyperproliferative processes will help the understanding of the events triggering cystogenesis. Our study will contribute to ongoing efforts assessing the therapeutic potential for cell cycle inhibitors in the treatment of ADPKD.
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