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Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function./
Author:	Kaddour, Nancy.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	165 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-05, Section: B.
Contained By:	Dissertations Abstracts International82-05B.
Subject:	Medicine. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28267088
ISBN:	9798691248580

Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function.
Kaddour, Nancy.

Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 165 p.

Source: Dissertations Abstracts International, Volume: 82-05, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Type 2 diabetes (T2D) is a complex, progressive disease that results from an interplay between genetic and environmental factors that unfavorably affect β-cell function and tissue insulin sensitivity. The rate of progression of the disease is mainly associated with β-cell abnormalities. A failure in β-cell compensation for prevailing tissue insulin resistance is the main trigger for T2D. Multiple factors lead to β-cell failure and eventual decompensation; those include hyperglycemia, hyperlipidemia, chronic β-cell stimulation and impaired incretin effect. These stressors combined with β-cell limited regenerative capacity will result in β-cell apoptosis, autophagy and dedifferentiation. Novel therapeutic avenues are currently focusing on characterizing regulators or growth factors that target β cells themselves.Our lab identified CCN5 as a matricellular protein that displays growth promoting effects in pancreatic β cells. We characterized CCN5 in whole genome cDNA microarray analysis of IGFI overexpressing islets. CCN5 was among the genes that were significantly upregulated in the islets of these mice. Furthermore, overexpression of CCN5 in MIN6 insulinoma cells enhanced the proliferation and survival of these cells. Collectively, these results raised our interest in CCN5'sphysiological effects in pancreatic β cells.For my PhD project, I hypothesize that CCN5/WISP2 is a growth factor that stimulates proliferation, survival and function of pancreatic β cells through the binding to a high-affinity receptor and activation of downstream targets. Thereby, I investigated the physiological effects ofCCN5 in pancreatic β cells using recombinant human CCN5 (rh-CCN5) insulinoma cells INS832/13, and primary mouse islets.We found that rh-CCN5 stimulated the proliferation of INS 832/13 and mouse islets via a pathway involving FAK/ERK activation and ultimately leading to the stimulation of cell cycle regulators CDK4 and Cyclin D1, respectively. Rh-CCN5 also protected INS 832/13 and mouse islets from lipotoxicity, glucolipotoxicity and streptozotocin (STZ) induced-cell death. The expression of key genes associated with β cells identity and function was also enhanced uponCCN5 addition in culture (Chapter II). We then showed a biphasic regulation of insulin secretion by CCN5 that seems to be dependent on the ER stress/UPR activity in these cells (Chapter III).Using ligand receptor capture technology, we identified neuronal acetylcholine receptor subunitalpha-3 (Chrna3) as a potential receptor for CCN5 on the surface of insulinoma MIN6 cells(Chapter IV). Finally, using microarray gene expression profiling, we identified novel CCN5targets in primary islets; those are involved in GPCR signaling, wound healing, and immune response (Chapter IV).These studies have confirmed the growth promoting properties of CCN5 in pancreatic β cells and characterized the mechanism by which CCN5 exerts such effects. Overall CCN5represents a potential candidate that could enhance β cells physiology in vitro and additional studies would be essential to validate its functions in vivo.

ISBN: 9798691248580Subjects--Topical Terms:

641104
Medicine.
Subjects--Index Terms:

Growth promoting properties of CCN5

Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function.
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245 1 0 $a Physiological Role of CCN5 in Pancreatic β-Cells: Effects on Proliferation, Survival and Insulin Secretory Function.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 165 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-05, Section: B.
500 $a Advisor: Liu, Jun-Li.
502 $a Thesis (Ph.D.)--McGill University (Canada), 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Type 2 diabetes (T2D) is a complex, progressive disease that results from an interplay between genetic and environmental factors that unfavorably affect β-cell function and tissue insulin sensitivity. The rate of progression of the disease is mainly associated with β-cell abnormalities. A failure in β-cell compensation for prevailing tissue insulin resistance is the main trigger for T2D. Multiple factors lead to β-cell failure and eventual decompensation; those include hyperglycemia, hyperlipidemia, chronic β-cell stimulation and impaired incretin effect. These stressors combined with β-cell limited regenerative capacity will result in β-cell apoptosis, autophagy and dedifferentiation. Novel therapeutic avenues are currently focusing on characterizing regulators or growth factors that target β cells themselves.Our lab identified CCN5 as a matricellular protein that displays growth promoting effects in pancreatic β cells. We characterized CCN5 in whole genome cDNA microarray analysis of IGFI overexpressing islets. CCN5 was among the genes that were significantly upregulated in the islets of these mice. Furthermore, overexpression of CCN5 in MIN6 insulinoma cells enhanced the proliferation and survival of these cells. Collectively, these results raised our interest in CCN5'sphysiological effects in pancreatic β cells.For my PhD project, I hypothesize that CCN5/WISP2 is a growth factor that stimulates proliferation, survival and function of pancreatic β cells through the binding to a high-affinity receptor and activation of downstream targets. Thereby, I investigated the physiological effects ofCCN5 in pancreatic β cells using recombinant human CCN5 (rh-CCN5) insulinoma cells INS832/13, and primary mouse islets.We found that rh-CCN5 stimulated the proliferation of INS 832/13 and mouse islets via a pathway involving FAK/ERK activation and ultimately leading to the stimulation of cell cycle regulators CDK4 and Cyclin D1, respectively. Rh-CCN5 also protected INS 832/13 and mouse islets from lipotoxicity, glucolipotoxicity and streptozotocin (STZ) induced-cell death. The expression of key genes associated with β cells identity and function was also enhanced uponCCN5 addition in culture (Chapter II). We then showed a biphasic regulation of insulin secretion by CCN5 that seems to be dependent on the ER stress/UPR activity in these cells (Chapter III).Using ligand receptor capture technology, we identified neuronal acetylcholine receptor subunitalpha-3 (Chrna3) as a potential receptor for CCN5 on the surface of insulinoma MIN6 cells(Chapter IV). Finally, using microarray gene expression profiling, we identified novel CCN5targets in primary islets; those are involved in GPCR signaling, wound healing, and immune response (Chapter IV).These studies have confirmed the growth promoting properties of CCN5 in pancreatic β cells and characterized the mechanism by which CCN5 exerts such effects. Overall CCN5represents a potential candidate that could enhance β cells physiology in vitro and additional studies would be essential to validate its functions in vivo.
520 $a Le diabete de type 2 (DT2) est une maladie complexe et progressive resultant del'interaction entre des facteurs genetiques et environnementaux. Cette maladie affecte la fonctiondes cellules-β ainsi que la sensibilite a l'insuline tissulaire. Le taux de progression de la maladieest principalement lie aux anomalies de la cellule-β. Une defaillance dans la compensation descellules-β, pour la resistance a l'insuline tissulaire predominante est le principal declencheur duDT2. De nombreux facteurs menent a la defaillance des cellules β et a leurs decompensationseventuelles tels que l'hyperglycemie, l'hyperlipidemie, la stimulation chronique et l'effet altere del'incretine. Ces facteurs de stress ainsi que la capacite limitee de regeneration des cellules β,entrainent l'apoptose, l'autophagie et la dedifferenciation. Les nouvelles voies therapeutiques seconcentrent presentement sur la caracterisation des regulateurs ou les facteurs de croissance ciblantles cellules β.Notre laboratoire a identifie CCN5 comme une proteine matricellulaire qui presente deseffets favorisants la croissance des cellules β pancreatiques. Nous avons caracterise CCN5 dansl'analyse par micropuce d'ADNc du genome entier des ilots surexprimant IGF-I. Nous avons ainsitrouve que CCN5 faisait partie des genes regules positivement dans les ilots de ces souris. De plus,la surexpression de CCN5 dans les cellules d'insulinome MIN6 a ameliore leurs taux deproliferations et survies. Par consequent, nous avons montre un interet pour les effetsphysiologiques de la CCN5 dans les cellules β pancreatiques.Pour mon projet de doctorat, j'ai formule une hypothese stipulant que la CCN5 / WISP2est un facteur de croissance qui stimule la proliferation, la survie et la fonction des cellules spancreatiques a travers un recepteur specifique ainsi que l'activation de cibles en aval. Nous avonsainsi etudie les effets physiologiques de la CCN5 dans les cellules β pancreatiques en utilisant la proteine recombinante humaine CCN5 (rh-CCN5), les cellules d'insulinome INS 832/13 et desilots de souris primaires.Nous avons constate que le rh-CCN5 stimule la proliferation d'INS 832/13 et d'ilots desouris via une voie impliquant l'activation de FAK/ERK, conduisant finalement a la stimulationdes regulateurs du cycle cellulaire CDK4 et Cycline D1 respectivement. Rh-CCN5 a aussi protegeINS 832/13 et les ilots des souris de la mort cellulaire induite par la lipotoxicite, laglucolipotoxicite et la streptozotocine (STZ), en regulant positivement l'expression de genes clesassocies a l'identite et a la fonction des cellules β (Chapitre II).Nous avons ensuite montre uneregulation biphasique de la secretion d'insuline par CCN5 qui semble dependre de l'activite destress ER/ UPR dans ces cellules (chapitre III). En utilisant la technologie de capture du recepteurde ligand, nous avons identifie la sous-unite alpha-3 (Chrna3) du recepteur de l'acetylcholineneuronale comme recepteur potentiel de CCN5 a la surface des cellules MIN6 de l'insulinome(Chapitre IV). Enfin, en utilisant le profil d'expression des genes de puces a ADN, nous avonsidentifie de nouvelles cibles CCN5 dans des ilots primaires, impliquees dans la signalisation duGPCR, la cicatrisation des plaies et la reponse immunitaire (Chapitre IV).Ces etudes ont confirme les proprietes promotrices de la croissance de CCN5 dans lescellules β pancreatiques et ont permis de caracteriser le mecanisme par lequel CCN5 exerce de telseffets. Globalement, CCN5 represente un candidat potentiel qui pourrait ameliorer la physiologiedes cellules β in vitro et des etudes supplementaires seraient fondamentales pour valider sesfonctions in vivo.
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650 4 $a Endocrinology. $3 610914
653 $a Growth promoting properties of CCN5
653 $a Type 2 diabetes
653 $a Insulin secretion
653 $a Induced-cell death
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710 2 $a McGill University (Canada). $3 1018122
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