Aneurysm contributes significantly to mortality in patients with polycystic kidney disease (PKD). Thus, a better understanding of vascular pathology in PKD may lead to prevention and treatment for these patients. Primary cilia are known to be the mechanosensory organelles in vascular endothelia. Emerging evidence indicates that primary cilia are involved in PKD pathogenesis. Using inducible-PKD models for endothelia, the proposed study is designed to ask if and how improving cilia function could diminish aneurysm formation. Therefore, our hypothesis is to test PKD models to determine if enhancing cilia function will significantly prevent aneurysm formation. Since our previous studies indicated that activation of ciliary dopamine receptor-5 (DR5) could enhance the mechanosensory function of primary cilia, our Aim 1 will use DR5 as a candidate model to explore our hypothesis, because this is the only model system known to increase cilia function at the present time. More specifically, this aim will examine the cellular mechanisms of primary cilia function in aneurysm in vitro and in vivo. Our previous studies also indicated that genomic instability and abnormal mitotic polarity contribute to aneurysm formation.
In Aim 2, we therefore ask if improving polyploidy and mitotic polarity could reduce aneurysm formation in vivo. The findings from these studies will provide useful information on the role of cilia in the regulation of vascular function and will generate new knowledge toward the understanding of vascular aneurysm.
There is currently no treatment for the prevention of aneurysm, and if left unchecked, aneurysm can cause stroke, paralysis and death. In addition to long-term care and limited medical intervention, stroke caused by an aneurysm rupture is a huge financial burden for our country, especially when we factor the loss of productivity from stroke patients. The goal of this proposal is to seek if and how we could avert aneurysm formation in order to prevent strokes, paralysis and death.
| Pala, Rajasekharreddy; Alomari, Nedaa; Nauli, Surya M (2017) Primary Cilium-Dependent Signaling Mechanisms. Int J Mol Sci 18: |
