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Surya M. Nauli - One of the best experts on this subject based on the ideXlab platform.
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The Roles of Primary Cilia in Cardiovascular Diseases
Cells, 2018Co-Authors: Rajasekharreddy Pala, Maha H. Jamal, Qamar Alshammari, Surya M. NauliAbstract:Primary Cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in Primary Cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary Cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial Cilia are involved in blood flow sensing. Dysfunction in endothelial Cilia contributes to aberrant fluid-sensing and thus results in vascular disorders, including hypertension, aneurysm, and atherosclerosis. This review focuses on the most recent findings on the roles of endothelial Primary Cilia within vascular biology and alludes to the possibility of Primary cilium as a therapeutic target for cardiovascular disorders.
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Calcium channels in Primary Cilia.
Current Opinion in Nephrology and Hypertension, 2016Co-Authors: Surya M. Nauli, Rajasekharreddy Pala, Steven J. KleeneAbstract:PURPOSE OF REVIEW Primary Cilia have become important organelles implicated in embryonic development, organogenesis, health, and diseases. Although many studies in cell biology have focused on changes in Ciliary length or ciliogenesis, the most common readout for evaluating Ciliary function is intracellular calcium. RECENT FINDINGS Recent tools have allowed us to examine intracellular calcium in more precise locations, that is, the cilioplasm and cytoplasm. Advances in calcium imaging have also allowed us to identify which Cilia respond to particular stimuli. Furthermore, direct electrophysiological measurement of ionic currents within a cilium has provided a wealth of information for understanding the sensory roles of Primary Cilia. SUMMARY Calcium imaging and direct measurement of calcium currents demonstrate that Primary Cilia are sensory organelles that house several types of functional calcium channels. Although intracellular calcium now allows a functional readout for Primary Cilia, discussions on the relative contributions of the several channel types have just begun. Perhaps, all of these calcium channels are required and necessary to differentiate stimuli in different microenvironments.
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Vascular Endothelial Primary Cilia: Mechanosensation and Hypertension.
Current hypertension reviews, 2016Co-Authors: Ashraf M. Mohieldin, Surya M. Nauli, Hannah C. Saternos, Hossain Saad Md Zubayer, Alzahra J. Al Omran, Ali A. Zarban, Wissam A. AboualaiwiAbstract:Primary Cilia are sensory organelles that extend from the cell surface and sense extracellular signals. Endothelial Primary Cilia protruding from the inner surface of blood vessel walls sense changes in blood flow and convert this mechanosensation into an intracellular biochemical/molecular signal, which triggers a cellular response. Primary endothelial Cilia dysfunction may contribute to the impairment of this response and thus be directly implicated in the development of vascular abnormalities such as hypertension and aneurysms. Using both in vitro techniques as well as in vivo animal models, we and others have investigated fluid flow mechanosensory functions of endothelial Cilia in cultured cells, animal models and autosomal dominant polycystic kidney disease (ADPKD) patients. More in-depth studies directed at identification of the mechanisms of fluid flow sensing will further enhance our knowledge of Cilia-dependent vascular pathology. Although the current treatments aimed at treating the cardiovascular symptoms in ADPKD patients successfully slowed the progression of cyst growth, there is growing evidence which suggests that drugs which interfere with Primary Cilia function or structure could reduce cardiovascular complications in ADPKD. This review is to summarize the most recent studies on Primary endothelial Cilia function in the vascular system and to present Primary Cilia as a novel therapeutic target for vascular hypertension.
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Calcium channels in Primary Cilia.
Current opinion in nephrology and hypertension, 2016Co-Authors: Surya M. Nauli, Rajasekharreddy Pala, Steven J. KleeneAbstract:Primary Cilia have become important organelles implicated in embryonic development, organogenesis, health, and diseases. Although many studies in cell biology have focused on changes in Ciliary length or ciliogenesis, the most common readout for evaluating Ciliary function is intracellular calcium. Recent tools have allowed us to examine intracellular calcium in more precise locations, that is, the cilioplasm and cytoplasm. Advances in calcium imaging have also allowed us to identify which Cilia respond to particular stimuli. Furthermore, direct electrophysiological measurement of ionic currents within a cilium has provided a wealth of information for understanding the sensory roles of Primary Cilia. Calcium imaging and direct measurement of calcium currents demonstrate that Primary Cilia are sensory organelles that house several types of functional calcium channels. Although intracellular calcium now allows a functional readout for Primary Cilia, discussions on the relative contributions of the several channel types have just begun. Perhaps, all of these calcium channels are required and necessary to differentiate stimuli in different microenvironments.
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Dopaminergic signaling within the Primary Cilia in the renovascular system.
Frontiers in Physiology, 2015Co-Authors: Kimberly F. Atkinson, Sarmed H. Kathem, Xingjian Jin, Wissam A. Aboualaiwi, Brian S. Muntean, Andromeda M. Nauli, Surya M. NauliAbstract:Activation of dopamine receptor type-5 (DR5) has been known to reduce systemic blood pressure, most likely by increasing renal vasodilation and enhancing natriuresis in the kidney. However, the mechanism of DR5 in natriuresis and vasodilation was not clearly known. We have previously shown that DR5 is localized to Primary Cilia of proximal renal epithelial and vascular endothelial cells. We here show that selective activation of DR5 specifically induces calcium influx only in the Primary Cilia, whereas non-selective activation of dopamine receptor induces calcium fluxes in both cilioplasm and cytoplasm. Cilia-independent signaling induced by thrombin only shows calcium signaling within cytoplasm. Furthermore, calcium activation in the cilioplasm by DR5 increases length and mechanosensory function of Primary Cilia, leading to a greater response to fluid-shear stress. We therefore propose a new mechanism by which DR5 induces vasodilation via chemical and mechanical properties that are specific to Primary Cilia.
Wissam A. Aboualaiwi - One of the best experts on this subject based on the ideXlab platform.
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Vascular Endothelial Primary Cilia: Mechanosensation and Hypertension.
Current hypertension reviews, 2016Co-Authors: Ashraf M. Mohieldin, Surya M. Nauli, Hannah C. Saternos, Hossain Saad Md Zubayer, Alzahra J. Al Omran, Ali A. Zarban, Wissam A. AboualaiwiAbstract:Primary Cilia are sensory organelles that extend from the cell surface and sense extracellular signals. Endothelial Primary Cilia protruding from the inner surface of blood vessel walls sense changes in blood flow and convert this mechanosensation into an intracellular biochemical/molecular signal, which triggers a cellular response. Primary endothelial Cilia dysfunction may contribute to the impairment of this response and thus be directly implicated in the development of vascular abnormalities such as hypertension and aneurysms. Using both in vitro techniques as well as in vivo animal models, we and others have investigated fluid flow mechanosensory functions of endothelial Cilia in cultured cells, animal models and autosomal dominant polycystic kidney disease (ADPKD) patients. More in-depth studies directed at identification of the mechanisms of fluid flow sensing will further enhance our knowledge of Cilia-dependent vascular pathology. Although the current treatments aimed at treating the cardiovascular symptoms in ADPKD patients successfully slowed the progression of cyst growth, there is growing evidence which suggests that drugs which interfere with Primary Cilia function or structure could reduce cardiovascular complications in ADPKD. This review is to summarize the most recent studies on Primary endothelial Cilia function in the vascular system and to present Primary Cilia as a novel therapeutic target for vascular hypertension.
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Abstract P101: The Role of Primary Cilia in Vascular Endothelial Cells
Hypertension, 2015Co-Authors: Hannah C. Saternos, Zubayer Hossain Saad, Wissam A. AboualaiwiAbstract:Primary Cilia are mechanosensory organelles that are projected into the lumen of blood vessels. It has been demonstrated that vascular endothelia require Primary Cilia to sense and transmit externa...
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Dopaminergic signaling within the Primary Cilia in the renovascular system.
Frontiers in Physiology, 2015Co-Authors: Kimberly F. Atkinson, Sarmed H. Kathem, Xingjian Jin, Wissam A. Aboualaiwi, Brian S. Muntean, Andromeda M. Nauli, Surya M. NauliAbstract:Activation of dopamine receptor type-5 (DR5) has been known to reduce systemic blood pressure, most likely by increasing renal vasodilation and enhancing natriuresis in the kidney. However, the mechanism of DR5 in natriuresis and vasodilation was not clearly known. We have previously shown that DR5 is localized to Primary Cilia of proximal renal epithelial and vascular endothelial cells. We here show that selective activation of DR5 specifically induces calcium influx only in the Primary Cilia, whereas non-selective activation of dopamine receptor induces calcium fluxes in both cilioplasm and cytoplasm. Cilia-independent signaling induced by thrombin only shows calcium signaling within cytoplasm. Furthermore, calcium activation in the cilioplasm by DR5 increases length and mechanosensory function of Primary Cilia, leading to a greater response to fluid-shear stress. We therefore propose a new mechanism by which DR5 induces vasodilation via chemical and mechanical properties that are specific to Primary Cilia.
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Non-motile Primary Cilia as fluid shear stress mechanosensors.
Methods in Enzymology, 2013Co-Authors: Surya M. Nauli, Xingjian Jin, Wissam A. Aboualaiwi, Wassim El-jouni, Jing ZhouAbstract:Primary Cilia are sensory organelles that transmit extracellular signals into intracellular biochemical responses. Structural and functional defects in Primary Cilia are associated with a group of human diseases, known as ciliopathies, with phenotypes ranging from cystic kidney and obesity to blindness and mental retardation. Primary Cilia mediate mechano- and chemosensation in many cell types. The mechanosensory function of the Primary Cilia requires the atypical G-protein-coupled receptor polycystin-1 and the calcium-permeable nonselective cation channel polycystin-2. Mechanical stimulations such as fluid-shear stress of the Primary Cilia initiate intracellular calcium rise, nitric oxide release, and protein modifications. In this review, we describe a set of protocols for cell culture to promote Ciliation, mechanical stimulations of the Primary Cilia, and measurements of calcium rise and nitric oxide release induced by fluid shear stress.
Yongjian Liu - One of the best experts on this subject based on the ideXlab platform.
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Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia
Journal of Biological Chemistry, 2016Co-Authors: Mingming Zhong, Xuwen Zhao, Wenjie Yuan, Gonghong Yan, Mingming Tong, Shuguang Guo, Yichao Zhu, Yong Jiang, Yongjian LiuAbstract:Folliculin (FLCN) is the tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a Ciliary protein that functions through Primary Cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to Primary Cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in Primary Cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through Primary Cilia.
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Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia
The Journal of biological chemistry, 2016Co-Authors: Mingming Zhong, Xuwen Zhao, Wenjie Yuan, Gonghong Yan, Mingming Tong, Shuguang Guo, Yichao Zhu, Yong Jiang, Yongjian LiuAbstract:Folliculin (FLCN) is the tumor suppressor associated with Birt-Hogg-Dubé (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a Ciliary protein that functions through Primary Cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to Primary Cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in Primary Cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through Primary Cilia.
Hiroshi Itoh - One of the best experts on this subject based on the ideXlab platform.
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HDAC2 promotes loss of Primary Cilia in pancreatic ductal adenocarcinoma.
EMBO Reports, 2016Co-Authors: Tetsuo Kobayashi, Kosuke Nakazono, Mio Tokuda, Yu Mashima, Brian David Dynlacht, Hiroshi ItohAbstract:Loss of Primary Cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose Primary Cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores Primary Cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of Primary Cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of Primary cilium formation in PDAC cells. ![][1] Loss of Primary Cilia is frequently observed in tumor cells. This study shows that histone deacetylase 2 (HDAC2) contributes to the suppression of Primary Cilia formation in pancreatic ductal adenocarcinoma (PDAC) cells by controlling Aurora A levels in a Kras‐independent manner. [1]: /embed/graphic-1.gif
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HDAC2 promotes loss of Primary Cilia in pancreatic ductal adenocarcinoma.
EMBO reports, 2016Co-Authors: Tetsuo Kobayashi, Kosuke Nakazono, Mio Tokuda, Yu Mashima, Brian David Dynlacht, Hiroshi ItohAbstract:Loss of Primary Cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose Primary Cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores Primary Cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of Primary Cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of Primary cilium formation in PDAC cells.
H Barry Collin - One of the best experts on this subject based on the ideXlab platform.
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Primary Cilia in vertebrate corneal endothelial cells.
Cell Biology International, 2004Co-Authors: Shaun P. Collin, H Barry CollinAbstract:The presence of Primary Cilia in corneal endothelial cells of a range of species from six non-mammalian vertebrate classes (Agnatha, Elasmobranchii, Amphibia, Teleostei, Reptilia and Aves) is examined by scanning and transmission electron microscopy. Our aim is to assess whether these non-motile Cilia protruding into the anterior chamber of the eye are a consistent phylogenetic feature of the corneal endothelium and if a quantitative comparison of their morphology is able to shed any new light on their function. The length (0.42–3.80 μm) and width (0.12–0.44 μm) of the Primary Cilia varied but were closely allied with previous studies in mammals. However, interspecific differences such as the presence of a terminal swelling in the Teleostei and Amphibia suggest there are functional differences. Approximately one-third of the endothelial cells possess Cilia but the extent of protrusion above the cell surface varies greatly, supporting a dynamic process of retraction and elongation. The absence of Primary Cilia in primitive vertebrates (Agnatha and Elasmobranchii) that possess other mechanisms to control corneal hydration suggests an osmoregulatory and/or chemosensory function.
