Polycystic kidney disease (PKD) is a systemic nephropathy characterized by progressive bilateral renal cyst formation that results in a gradual decline in renal function. Although it is most commonly categorized as a kidney disease, the majority of patients with PKD die due to cardiovascular complications such as hypertension, aneurysm, hemorrhage, etc. Nonetheless, very little attention has been focused on the basic science aspects of these complications. We believe that PKD is associated with both genetic and functional defects in mechanosensory cilia, causing aberrant calcium signaling that lead to cardiovascular complications. Here, we hypothesize that primary cilia play an important role in fluid-shear sensing in endothelial cells. Using endothelial cells from Pkd mouse models (such as Tg737, Pkd1, and Pkd2), we will study whether Pkd endothelial cells have biomechanical dysfunction in fluid-shear sensing similar to those previously demonstrated in Pkd epithelial cells. We will further study whether cilia, acting as mechanical-sensory organelles, have unique biophysical abilities to sense fluid-shear stress. Given that all cells are capable of sensing extracellular signals, we intend to ask how specific is the mechanical sensing by cilia. We will use a set of different stimuli to examine the specificity of cilia in fluid-shear sensing. We will compare cellular responses induced by fluid-shear stress, plasma membrane distortion, and pharmacological ligands. We will use both biophysical (calcium) and biochemical (nitric oxide) properties of endothelial cells to study their involvement in mechanofluid sensing. Thus, the present proposal is positioned to provide new insights into mechanisms of cardiovascular diseases, such as hypertension, in both PKD and non-PKD patients. The proposed study will also advance scientific understanding of cilia biology in fluid sensing related to cardiovascular physiology and pathophysiology.
Although PKD is often described as one of the most common human genetic diseases;only 4% of the cases of new end-stage renal disease (ESRD) have been in the cystic disease category. On the other hand, hypertension is the second most common cause of ESRD and is one of the leading causes of cardiovascular death. Because the pathogenesis of hypertension in PKD is still unknown, the present proposal is designed to understand the molecular pathology of hypertension and to offer information enabling more precise and specific pharmacological interventions with the potential to effectively treat or reduce high blood pressure.
| Omran, Alzahra J Al; Saternos, Hannah C; Althobaiti, Yusuf S et al. (2017) Alcohol consumption impairs the ependymal cilia motility in the brain ventricles. Sci Rep 7:13652 |
| Atkinson, Kimberly F; Nauli, Surya M (2016) pH sensors and ion Transporters: Potential therapeutic targets for acid-base disorders. Int J Pharma Res Rev 5:51-58 |
| Kathem, Sarmed H; AbouAlaiwi, Wissam A; Zi, Xiaolin et al. (2016) Capillary endothelia from two ADPKD patients are polyploidy. Ann Clin Cytol Pathol 2: |
| Grimes, Daniel T; Keynton, Jennifer L; Buenavista, Maria T et al. (2016) Genetic Analysis Reveals a Hierarchy of Interactions between Polycystin-Encoding Genes and Genes Controlling Cilia Function during Left-Right Determination. PLoS Genet 12:e1006070 |
| Al Omran, Alzahra J; Saternos, Hannah C; Liu, Tongyu et al. (2015) Live Imaging of the Ependymal Cilia in the Lateral Ventricles of the Mouse Brain. J Vis Exp :e52853 |
| Mohieldin, Ashraf M; Haymour, Hanan S; Lo, Shao T et al. (2015) Protein composition and movements of membrane swellings associated with primary cilia. Cell Mol Life Sci 72:2415-29 |
| Mohieldin, Ashraf M; AbouAlaiwi, Wissam A; Gao, Min et al. (2015) Chemical-Free Technique to Study the Ultrastructure of Primary Cilium. Sci Rep 5:15982 |
| Aboualaiwi, Wissam A; Muntean, Brian S; Ratnam, Shobha et al. (2014) Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. Circulation 129:660-72 |
| Kathem, Sarmed H; Mohieldin, Ashraf M; Abdul-Majeed, Shakila et al. (2014) Ciliotherapy: a novel intervention in polycystic kidney disease. J Geriatr Cardiol 11:63-73 |
| Muntean, Brian S; Jin, Xingjian; Williams, Frederick E et al. (2014) Primary cilium regulates CaV1.2 expression through Wnt signaling. J Cell Physiol 229:1926-34 |
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