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UV-Induced DNA Damage and Repair: The Role of Melanin and the MC1R GeneHauser, Jennifer E. 03 April 2006 (has links)
No description available.
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Local Anesthetic Efficacy of the Inferior Alveolar Nerve Block in Red-haired FemalesDroll, Brock A. 15 December 2011 (has links)
No description available.
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Cloning, Expression, Pharmacological Characterization and Anatomical Distribution of Melanocortin Receptors in an Evolutionary PerspectiveRingholm, Aneta I. January 2004 (has links)
<p>The melanocortin (MC) receptors are G-protein coupled receptors thatparticipate in several important physiological functions such as the regulation of the energy balance. This thesis focuses on the evolutionary aspect of the MC receptors and their pharmacology.</p><p>One MC4 receptor and two MC5 receptor subtypes were found in a teleost fish, zebrafish. This indicates that the MC receptor subtypes arose very early in vertebrate evolution. Important pharmacological and functional properties, as well as gene structure and syntenic relationships have been highly conserved over a period of more than 400 million years implying that these receptors participate in vital physiological functions. Moreover, we found a MC4 receptor from a shark, spiny dogfish that represents the most distant MC receptor gene cloned to date. We also characterized the pharmacology of a MC4 receptor in goldfish. The conserved central expression pattern and physiological role in regulation of food intake of the MC4 receptor suggests that neuronal pathways of the melanocortin system may be important for regulation of energy homeostasis in most vertebrates. We determined the chromosomal position of the chicken MC receptors genes and found conserved synteny of the MC2, MC5, and MC4 receptor genes. These results suggest that there exist a clustering of these genes that is ancient. Analysis of conserved synteny with mammalian genomes and paralogon segments prompted us to predict an ancestral gene organization that may explain how this family has been formed through both local duplication and tetraploidization processes.</p><p>There are several common point mutations in the human MC1 receptor that are over represented in North European red-heads, and in individuals with pale skin. We pharmacologically characterised four naturally occurring human MC1 receptor variants providing molecular explanation to the respective phenotype.</p><p>The MC receptor subtypes have highly diverse physiological functions despite having relative high similarities in their primary structure. Our studies on the structural and functional properties of the MC receptor subtypes have provided insight into the molecular mechanism of how the specification of these receptors may have occurred.</p>
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Cloning, Expression, Pharmacological Characterization and Anatomical Distribution of Melanocortin Receptors in an Evolutionary PerspectiveRingholm, Aneta I. January 2004 (has links)
The melanocortin (MC) receptors are G-protein coupled receptors thatparticipate in several important physiological functions such as the regulation of the energy balance. This thesis focuses on the evolutionary aspect of the MC receptors and their pharmacology. One MC4 receptor and two MC5 receptor subtypes were found in a teleost fish, zebrafish. This indicates that the MC receptor subtypes arose very early in vertebrate evolution. Important pharmacological and functional properties, as well as gene structure and syntenic relationships have been highly conserved over a period of more than 400 million years implying that these receptors participate in vital physiological functions. Moreover, we found a MC4 receptor from a shark, spiny dogfish that represents the most distant MC receptor gene cloned to date. We also characterized the pharmacology of a MC4 receptor in goldfish. The conserved central expression pattern and physiological role in regulation of food intake of the MC4 receptor suggests that neuronal pathways of the melanocortin system may be important for regulation of energy homeostasis in most vertebrates. We determined the chromosomal position of the chicken MC receptors genes and found conserved synteny of the MC2, MC5, and MC4 receptor genes. These results suggest that there exist a clustering of these genes that is ancient. Analysis of conserved synteny with mammalian genomes and paralogon segments prompted us to predict an ancestral gene organization that may explain how this family has been formed through both local duplication and tetraploidization processes. There are several common point mutations in the human MC1 receptor that are over represented in North European red-heads, and in individuals with pale skin. We pharmacologically characterised four naturally occurring human MC1 receptor variants providing molecular explanation to the respective phenotype. The MC receptor subtypes have highly diverse physiological functions despite having relative high similarities in their primary structure. Our studies on the structural and functional properties of the MC receptor subtypes have provided insight into the molecular mechanism of how the specification of these receptors may have occurred.
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Exploration de la plasticité neuronale et gliale dans le système à mélanocortine à l'échelle des repas dans un modèle murin. / Exploration of neuronal and glial plasticity in the melanocortin system at the meal in a mouse model.Nuzzaci, Danaé 12 December 2017 (has links)
En 2015, la revue Nature a publié la plus grande étude d’association pangénomique à ce jour reliant des variants génétiques à l’indice de masse corporelle. Cette étude a mis en avant le rôle du système nerveux central dans la vulnérabilité à l’obésité, et soutient un concept original selon lequel la plasticité cérébrale jouerait un rôle important dans le contrôle de la balance énergétique. Ainsi, des capacités de plasticité cérébrale réduites pourraient favoriser des comportements alimentaires inadaptés, ce qui augmenterait le risque de prise de poids sous pression calorique. Les neurones anorexigènes POMC et les neurones orexigènes AgRP qui composent le système à mélanocortine et qui contrôlent la balance énergétique, conservent effectivement des propriétés de plasticité synaptique dans le cerveau adulte. Celles-ci se manifestent en réponse à des fluctuations hormonales intenses, induites par des manipulations génétiques, chirurgicales ou nutritionnelles drastiques. Cependant le rôle physiologique de cette plasticité synaptique au sein du système à mélanocortine n’a pas encore été démontré. Nos résultats montrent que des phénomènes de plasticité cérébrale sont récapitulés à l’échelle des repas chez la souris, en fonction de l’état prandial, en réponse à des changements métaboliques et hormonaux modérés. En effet, une exposition à 1h de régime standard augmente l’activité électrique des neurones POMC, ce qui est corrélé à une rétractation de la couverture astrocytaire autour des somas POMC, sans changement de configuration synaptique par rapport à l’état préprandial. A l’opposé, une exposition à 1h de régime riche en lipides ne modifie pas l’activité électrique des neurones POMC et n’entraine pas de rétractation de la couverture astrocytaire. De plus, par blocage pharmacologique de l’hyperglycémie post-prandiale, nous avons montré que le glucose était nécessaire pour initier la rétractation gliale post-prandiale. Enfin, par une approche pharmacogénétique, nous avons montré que l’inactivation des astrocytes modifie le comportement alimentaire et diminue la couverture astrocytaire autour des neurones POMC. Ces résultats suggèrent que l’astrocyte jouerait un rôle inhibiteur sur l’activité électrique des neurones POMC et que la rétractation astrocytaire post-prandiale, autour des somas POMC lèverait l’inhibition des neurones POMC et favoriserait la sensation de satiété. Ce mode de régulation ne serait pas déclenché lors d’un repas riche en graisses, ce qui expliquerait le faible pouvoir satiétogène de ce type de repas. / In 2015, Nature published the largest pangenomic association study to date linking genetic variants to body mass index. This study highlighted the role of the central nervous system in vulnerability to obesity and supports an original concept that cerebral plasticity plays an important role in the control of energy balance. Thus, reduced cerebral plasticity capacities could lead to inadequate dietary behaviors, which would increase the risk of weight gain under caloric pressure. The anorectic neurons POMC and the orexigenic neurons AgRP of the melanocortin system, which control the energy balance, actually show synaptic plasticity properties in the adult brain. These phenomena are shown in response to intense hormonal fluctuations induced by drastic genetic, surgical or nutritional manipulations. However, the physiological role of this synaptic plasticity within the melanocortin system has not been demonstrated yet. This study shows that cerebral plasticity phenomena are recapitulated at the meal scale in mice, depending on the prandial state, in response to moderate metabolic and hormonal changes. Indeed, 1 h standard diet exposure increases the electrical activity of the POMC neurons, which is correlated with a retraction of the astrocytic coverage around the POMC somas, with no change in synaptic configuration compared to the preprandial state. In contrast, 1 hour of high fat diet exposure does not modify the electrical activity of the POMC neurons and does not involve retraction of the astrocytic coverage. In addition, by pharmacological blockade of postprandial hyperglycemia, we showed that glucose is required for postprandial glial retraction. Finally, by a pharmacogenetic approach, we have shown that the inactivation of astrocytes modifies the feeding behavior and decreases the astrocytic coverage around the POMC neurons. These results suggest i)that astrocytes would play an inhibitory role on the electrical activity of POMC neurons ii) and that the post-prandial astrocytic retraction around POMC somas might remove inhibition of POMC neurons and might promote the sensation of satiety. This mode of regulation would not be activated during a high-fat meal, which would explain the low satietogenic properties of this type of meal.
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Altérations hypothalamiques dans la sclérose latérale amyotrophique / Hypothalamic alterations in amyotrophic lateral sclerosisVercruysse, Pauline 28 September 2016 (has links)
La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative due à la dégénérescence des motoneurones supérieurs et inférieurs. La perte des neurones moteurs entraine une atrophie puis une paralysie progressive des muscles. En plus de la perte musculaire, une perte de poids est importante chez les patients SLA. Ce symptôme apparaît avant les premiers symptômes moteurs et est corrélé avec la survie. Ce défaut du métabolisme énergétique est en partie dû à un hypermétabolisme associé à des problèmes de prise alimentaire. L’hypothalamus est la partie du cerveau contrôlant l’ensemble du métabolisme énergétique. L’objectif de ma thèse a été de caractériser les altérations hypothalamiques dans la SLA. Nous avons tout d’abord mis en évidence une anomalie du système mélanocortine de l’hypothalamus, et montré que cette anomalie était associée à des modifications du comportement alimentaire. Ensuite, nos travaux ont mis en évidence une atrophie de la partie postérieure de l’hypothalamus, comprenant l’aire hypothalamique latérale (LHA), des patients SLA, corrélée à la perte de poids. Finalement, nous démontré que les neurones produisant le MCH, situés dans le LHA, sont atteints dans la SLA et qu’une complémentation en MCH empêche la perte de poids dans un modèle animal de SLA. / Amyotrophic Lateral Sclerosis (ALS) is a major neurodegenerative disease characterised by a loss of upper and lower motor neurons. The loss of motor neurons leads to muscle atrophy and paralysis. Besides motor loss, weight loss is important in ALS patients. This symptom appears before first muscular symptoms and is correlated with survival. This defect of energetic metabolism is partially due to hypermetabolism associated with food intake problems. Hypothalamus is the part of brain controlling the energetic metabolism. The aim of my Ph.D. was to characterise hypothalamic alterations in ALS. First, we have shown a default in the melanocortin system of hypothalamus, and shown that this melanocortin defect correlates with alterations in food intake behaviour. Second, we demonstrated the existence of hypothalamic atrophy in ALS patients in the posterior part of the hypothalamus, including the lateral hypothalamic area (LHA). This atrophy was correlated with weight loss. Finally, we observed that hypothalamic MCH neurons, located in the LHA, are affected in ALS, and that MCH complementation rescues weight loss in a mouse model of ALS.
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Modeling the Interaction Space of Biological Macromolecules: A Proteochemometric Approach : Applications for Drug Discovery and DevelopmentKontijevskis, Aleksejs January 2008 (has links)
<p>Molecular interactions lie at the heart of myriad biological processes. Knowledge of molecular recognition processes and the ability to model and predict interactions of any biological molecule to any chemical compound are the key for better understanding of cell functions and discovery of more efficacious medicines.</p><p>This thesis presents contributions to the development of a novel chemo-bioinformatics approach called proteochemometrics; a general method for interaction space analysis of biological macromolecules and their ligands. In this work we explore proteochemometrics-based interaction models over broad groups of protein families, evaluate their validity and scope, and compare proteochemometrics to traditional modeling approaches.</p><p>Through the proteochemometric analysis of large interaction data sets of multiple retroviral proteases from various viral species we investigate complex mechanisms of drug resistance in HIV-1 and discover general physicochemical determinants of substrate cleavage efficiency and binding in retroviral proteases. We further demonstrate how global proteochemometric models can be used for design of protease inhibitors with broad activity on drug-resistant viral mutants, for monitoring drug resistance mechanisms in the physicochemical sense and prediction of potential HIV-1 evolution trajectories. We provide novel insights into the complexity of HIV-1 protease specificity by constructing a generalized IF-THEN rule model based on bioinformatics analysis of the largest set of HIV-1 protease substrates and non-substrates.</p><p>We discuss how proteochemometrics can be used to map recognition sites of entire protein families in great detail and demonstrate how it can incorporate target variability into drug discovery process. Finally, we assess the utility of the proteochemometric approach in evaluation of ADMET properties of drug candidates with a special focus on inhibition of cytochrome P450 enzymes and investigate application of the approach in the pharmacogenomics field.</p>
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Descoberta de ligantes do receptor de melanocortina-5 (MC5R) como candidatos a moduladores da sebogênese: estudos de modelagem por homologia, triagem virtual e ensaio celular / Discovery of ligands for the melanocortin-5 receptor (MC5R) as candidates of modulators of sebogenesis: homology modeling studies, virtual screening and cellular assayKatekawa, Edson 20 November 2018 (has links)
A acne é uma condição da pele multifatorial com implicações socioeconômicas importantes. Um dos principais fatores que contribuem com a sua etiologia é a superprodução de sebo. Até o momento, há poucos tratamentos seguros e eficazes disponíveis. O receptor de melanocortina-5 (MC5R), um receptor acoplado à proteína G da família das rodopsinas, é uma das proteínas responsáveis pela diferenciação de sebócitos e consequente produção de sebo, mas não há opções de tratamento através do antagonismo deste receptor. Neste trabalho, investigamos a melanocortina-5 como alvo molecular para a descoberta de ligantes como moduladores da sebogênese. Para tanto, empregamos estudos de modelagem por homologia e triagem virtual baseada em estrutura do alvo para construir um modelo 3D da MC5R e identificar de candidatos a ligantes da proteína, respectivamente. Em seguida, avaliamos o potencial de inibição da sebogênese em sebócitos SEBO662AR em meio lipogênico. Os resultados obtidos indicaram a descoberta de peptídeos e flavonoides com características inibidoras e estimuladoras da produção de sebo. Novos esqueletos moleculares foram identificados como promissores para a modulação da sebogênese. Os estudos realizados permitirão o desenvolvimento de novos ativos dermatológicos e cosméticos com potencial de modular a oleosidade da pele, de modo a contribuir com a mitigação dos efeitos da acne, psoríase, alopecia e seborreia, entre outras doenças. / Acne is a multifactorial skin condition with important socioeconomic implications. One of the main factors that contribute with its etiology is sebum overproduction. Until now, there are few safe, effective treatments available. Melanocortin-5 receptor (MC5R), a G protein-coupled receptor of the rhodopsin family, is one of the proteins responsible for sebocyte differentiation and consequent sebum production, but there are no options for treatment by antagonism of this receptor. In this work, we investigated MC5R as molecular target for the discovery of ligands as sebogenesis modulators. For that, we used homology modeling studies, and structure-based virtual screening in order to, respectively, build a MC5R 3D model and identify ligand candidates for this protein. Then, we evaluated their sebogenesis inhibition potential on SEBO662AR sebocytes in lipogenic conditions. The obtained results indicated the discovery of peptides and flavonoids with inhibitory and stimulatory sebum production characteristics. New scaffolds were identified as promising for sebogenesis modulation. The performed studies will allow the development of novel dermatologic and cosmetic actives with the potential to modulate skin oiliness in order to contribute to the mitigation of the effects of acne, psoriasis, alopecia and seborrhea, among other diseases.
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Modeling the Interaction Space of Biological Macromolecules: A Proteochemometric Approach : Applications for Drug Discovery and DevelopmentKontijevskis, Aleksejs January 2008 (has links)
Molecular interactions lie at the heart of myriad biological processes. Knowledge of molecular recognition processes and the ability to model and predict interactions of any biological molecule to any chemical compound are the key for better understanding of cell functions and discovery of more efficacious medicines. This thesis presents contributions to the development of a novel chemo-bioinformatics approach called proteochemometrics; a general method for interaction space analysis of biological macromolecules and their ligands. In this work we explore proteochemometrics-based interaction models over broad groups of protein families, evaluate their validity and scope, and compare proteochemometrics to traditional modeling approaches. Through the proteochemometric analysis of large interaction data sets of multiple retroviral proteases from various viral species we investigate complex mechanisms of drug resistance in HIV-1 and discover general physicochemical determinants of substrate cleavage efficiency and binding in retroviral proteases. We further demonstrate how global proteochemometric models can be used for design of protease inhibitors with broad activity on drug-resistant viral mutants, for monitoring drug resistance mechanisms in the physicochemical sense and prediction of potential HIV-1 evolution trajectories. We provide novel insights into the complexity of HIV-1 protease specificity by constructing a generalized IF-THEN rule model based on bioinformatics analysis of the largest set of HIV-1 protease substrates and non-substrates. We discuss how proteochemometrics can be used to map recognition sites of entire protein families in great detail and demonstrate how it can incorporate target variability into drug discovery process. Finally, we assess the utility of the proteochemometric approach in evaluation of ADMET properties of drug candidates with a special focus on inhibition of cytochrome P450 enzymes and investigate application of the approach in the pharmacogenomics field.
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Gene Expression in the Brains of Two Lines of Chicken Divergently Selected for High and Low Body WeightKa, Sojeong January 2009 (has links)
Artificial divergent selection of chickens for high and low body weight at 8 weeks of age has produced two lines: the high (HWS) and low (LWS) body weight chicken lines. In addition to the difference in body weight, the lines show extreme differences in feeding behaviour and body composition. The aim of this study was to uncover the genetic and molecular factors that contribute to and determine these differences, especially regarding body energy regulation and appetite. In papers I and II, genome-wide gene expression in a brain sample containing hypothalamus and in dissected hypothalamus was analysed using DNA microarray and qRT-PCR. We found that levels of differential expression were generally moderate, which was consistent with the idea that polygenic factors were involved in the establishment of the chicken lines. Genes associated with neural plasticity, lipid metabolism and body energy regulation were differentially expressed. This result indicated that the neural systems regulating feeding behaviour and body weight were altered in the chicken lines. However, genes that were involved in the central melanocortin system were not systematically differentially expressed. Interestingly, the biggest differences in expression between the lines found in endogenous retrovirus sequences of the ALV subgroup E. Thus, in paper III, we characterized the number of integrations, the expression of ALVE retroviral elements and their effects on body weight. A significant correlation between low body weight and high ALVE expression was observed in female F9 birds from an HWS x LWS advanced intercross line. This implied that ev-loci contributing to increased ALVE expression levels were genetically linked to loci influencing the low body weight of the pullets. In paper IV, the carnitine palmitoyltransferase-1b gene (CPT1B), which was highly differentially expressed in the hypothalami, was investigated. We mapped chicken CPT1B to the distal tip of chromosome 1p. The levels of CPT1B mRNA in the HWS line were higher in the hypothalamus and lower in muscle than in the LWS line. This pattern of differential expression indicates that this gene could contribute to the remarkable phenotypic differences between HWS and LWS chickens. However, comparison with quantitative trait loci data showed that the expression of CPT1B is a trans effect, rather than a direct causative locus. In conclusion, the data suggested that the long-term selection for body weight resulted in differential gene expression in the brains of the selected chicken lines. These results may have relevance for the poultry industry and will also contribute to increasing knowledge about human diseases such as obesity and anorexia.
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