The Roles Of Primary Cilia In Cardiovascular System
Surya Nauli
Pharmacologyuniversity Of Toledo
Grant 1R01DK080640-01A1 from National Institute Of Diabetes And Digestive And Kidney Diseases, IRG: VCMB
Abstract: 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. theless, 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. PUBLIC HEALTH RELEVANCE 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
Project start date: 2008-08-01
Project end date: 2013-07-31
Sponsored Links Lab Supply Mall http://www.labsupplymall.com
Grants awarded to Surya Nauli
The Roles Of Primary Cilia In Cardiovascular System
Surya Nauli
Pharmacologyuniversity Of Toledo
Grant 1R01DK080640-01A1 from National Institute Of Diabetes And Digestive And Kidney Diseases, IRG: VCMB
Abstract: 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. theless, 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. PUBLIC HEALTH RELEVANCE 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
Project start date: 2008-08-01
Project end date: 2013-07-31
Related Publications
Ciliary dysfunction in polycystic kidney disease: an emerging model with polarizing potential. Front Biosci. 2008 May 1; 13: 4451-66. Review. PMID: 18508522 Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1. Circulation. 2008 Mar 4; 117( 9): 1161-71. Epub 2008 Feb 19. PMID: 18285569 
Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. Mol Cell Biol. 2007 Apr; 27( 8): 3241-52. Epub 2007 Feb 5. PMID: 17283055 
Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol. 2006 Apr; 17( 4): 1015-25. PMID: 16565258 Molecular changes in nNOS protein expression within the ventrolateral medulla following transient focal ischemia affect cardiovascular functions. Brain Res. 2005 Sep 7; 1055( 1-2): 73-82. PMID: 16084499 Chronic hypoxia modulates relations among calcium, myosin light chain phosphorylation, and force differently in fetal and adult ovine basilar arteries. J Appl Physiol. 2005 Jul; 99( 1): 120-7. PMID: 16036903 Involvement of extracellular Ca2+ influx through voltage-independent Ca2+ channels in endothelin-1 function. Cell Signal. 2005 Aug; 17( 8): 911-6. Epub 2005 Feb 16. Review. PMID: 15894164 Global cytoskeletal control of mechanotransduction in kidney epithelial cells. Exp Cell Res. 2004 Nov 15; 301( 1): 23-30. PMID: 15501441 Polycystins and mechanosensation in renal and nodal cilia. Bioessays. 2004 Aug; 26( 8): 844-56. Review. PMID: 15273987 Gating of the polycystin ion channel signaling complex in neurons and kidney cells. FASEB J. 2004 Apr; 18( 6): 740-2. Epub 2004 Feb 6. PMID: 14766803 Cardiovascular responses and neurotransmitter changes following blockade of nNOS within the ventrolateral medulla during static muscle contraction. Brain Res. 2003 Jul 4; 977( 1): 80-9. PMID: 12788516 Immortalized epithelial cells from human autosomal dominant polycystic kidney cysts. Am J Physiol Renal Physiol. 2003 Sep; 285( 3): F397-412. Epub 2003 May 6. PMID: 12734101 Maturation alters cyclic nucleotide and relaxation responses to nitric oxide donors in ovine cerebral arteries. Biol Neonate. 2003; 83( 2): 123-35. PMID: 12576757 Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003 Feb; 33( 2): 129-37. Epub 2003 Jan 6. PMID: 12514735 Cardiovascular responses and neurotransmission in the ventrolateral medulla during skeletal muscle contraction following transient middle cerebral artery occlusion and reperfusion. Brain Res. 2002 Oct 18; 952( 2): 176-87. PMID: 12376178 Maturation alters the contribution of potassium channels to resting and 5HT-induced tone in small cerebral arteries of the sheep. Brain Res Dev Brain Res. 2002 Feb 28; 133( 2): 81-91. PMID: 11882339