The obesity associated with agouti-yellow mouse ap-640 Memorial Drive pears to be the consequence... more The obesity associated with agouti-yellow mouse ap-640 Memorial Drive pears to be the consequence of ectopic expression of Cambridge, Massachusetts 02139 a secreted protein encoded by the A locus. The mutation † McLaughlin Research Institute underlying the fat phenotype has been shown to be for Biomedical Sciences within the gene encoding carboxypeptidase E (CPE), 1520 23rd Street South a prehormone-processing enzyme. The mechanism by Great Falls, Montana 59405 which the fat and A y mutations result in obesity is not yet understood. Classical parabiosis experiments suggested that ob encodes a circulating factor and that db Summary may encode the receptor for the OB protein (Coleman, 1973). The recent cloning of these genes appears to The mutated gene responsible for the tubby obesity confirm these predictions. ob encodes a secreted prophenotype has been identified by positional cloning. tein (leptin) that may function to signal fat depot levels A single base change within a splice donor site results to the brain and other tissues (Campfield et al., 1995). in the incorrect retention of a single intron in the ma-The db locus encodes a high affinity receptor for leptin ture tub mRNA transcript. The consequence of this (OB-R; Chen et al., 1996). OB-R is a single membranemutation is the substitution of the carboxy-terminal spanning receptor most closely related to the gp130 44 amino acids with 24 intron-encoded amino acids. cytokine receptor signal-transducing component (Tar-The normal transcript appears to be abundantly extaglia et al., 1995). pressed in the hypothalamus, a region of the brain Coleman and Eicher (1990) reported an autosomal involved in body weight regulation. Variation in the recessive mutation for obesity in mouse. This mutation, relative abundance of alternative splice products is called tubby (tub) arose spontaneously in a C57BL/6J observed between inbred mouse strains and appears colony. This is the only known allele of tub. Homozygous to correlate with an intron length polymorphism. This tub/tub mice, depending on sex and strain background, allele of tub is a candidate for a previously reported are recognizable by increased body weight at three to diet-induced obesity quantitative trait locus on mouse six months of age. Once the weight gain is apparent, it chromosome 7. is rapidly progressive and often results in animals that weigh twice as much as their littermate controls. Matu-Introduction rity-onset obesity is also characteristic of the fat mouse and is reminiscent of the pattern of weight gain com-Obesity (an abnormally high percentage of body fat relamonly observed in human populations. In contrast, tive to lean tissue mass) is strongly associated with a obese and diabetes mice begin rapid weight gain soon number of common diseases that have a major impact after birth. on morbidity and mortality including type II diabetes, Tubby mice develop insulin resistance with their hypertension, cardiovascular disease, hyperlipidaemia, weight gain but do not progress to overt diabetes. Conand some cancers (Grundy and Barnett, 1990). sistent with the absence of diabetes is the normal pa-Genetic approaches provide one strategy for defining thology observed in histological examination of a tubby the molecular components of the pathways involved in pancreas (Coleman and Eicher, 1990). In spite of the the regulation of body weight. In human populations, fact that the tubby obese phenotype is inherited in a the existence of a number of rare single-gene disorders recessive manner, some significant differences in lipid strongly associated with obesity, such as Bardet-Biedl profiles and susceptibility to atherosclerosis have been syndrome (Kwitek-Black et al., 1993) or the contiguous reported in tub heterozygotes (Nishina et al., 1994a, gene syndrome known as Prader-Willi syndrome (re-1994b). When fed an atherogenic diet, tub heterozygotes viewed in Knoll et al., 1993), suggests that genetic mechwere found to have significantly raised levels of plasma anisms can influence body weight. Susceptibility to obetriglycerides and a reduced susceptibility to aortic fatty sity in the general population appears to be a complex streak lesions, suggesting that there may be dominant trait, and a significant genetic component has been effects of the tub mutation. The influence of strain background on the susceptibility of tubby animals to diabetes, dyslipidemia, or atherosclerosis is unclear.
L'invention se rapporte a l'identification de nouvelles molecules d'acide nucleique e... more L'invention se rapporte a l'identification de nouvelles molecules d'acide nucleique et de proteines codees par ces dernieres ou leurs variants degeneres, qui sont actives dans le controle du poids corporel des mammiferes. Les molecules d'acide nucleique de l'invention representent les genes correspondant au gene tub mammifere, un gene qui est implique dans la regulation du poids du corps.
This paper applies objective methods to explore the technological origins of the widely acclaimed... more This paper applies objective methods to explore the technological origins of the widely acclaimed CRISPR breakthrough in the technological domain of genome engineering. Previously developed patent search techniques are first used to recover a set of patents that well-represent the genome editing domain before CRISPR. Main paths are then determined from the citation network associated with this patent set allowing identification of the three major knowledge trajectories. The most significant of these trajectories for CRISPR involves the core of genome editing with less significant trajectories involving cloning and endonuclease specific developments. The major patents on the core trajectory are consistent with qualitative expert knowledge of the topical area. A second set of patents that we call the CRISPR roots are obtained by finding the patents directly cited by the recent CRISPR patents along with patents cited by that set of patents. We find that the CRISPR roots contain 8 key p...
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation,... more In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
The obesity associated with agouti-yellow mouse ap-640 Memorial Drive pears to be the consequence... more The obesity associated with agouti-yellow mouse ap-640 Memorial Drive pears to be the consequence of ectopic expression of Cambridge, Massachusetts 02139 a secreted protein encoded by the A locus. The mutation † McLaughlin Research Institute underlying the fat phenotype has been shown to be for Biomedical Sciences within the gene encoding carboxypeptidase E (CPE), 1520 23rd Street South a prehormone-processing enzyme. The mechanism by Great Falls, Montana 59405 which the fat and A y mutations result in obesity is not yet understood. Classical parabiosis experiments suggested that ob encodes a circulating factor and that db Summary may encode the receptor for the OB protein (Coleman, 1973). The recent cloning of these genes appears to The mutated gene responsible for the tubby obesity confirm these predictions. ob encodes a secreted prophenotype has been identified by positional cloning. tein (leptin) that may function to signal fat depot levels A single base change within a splice donor site results to the brain and other tissues (Campfield et al., 1995). in the incorrect retention of a single intron in the ma-The db locus encodes a high affinity receptor for leptin ture tub mRNA transcript. The consequence of this (OB-R; Chen et al., 1996). OB-R is a single membranemutation is the substitution of the carboxy-terminal spanning receptor most closely related to the gp130 44 amino acids with 24 intron-encoded amino acids. cytokine receptor signal-transducing component (Tar-The normal transcript appears to be abundantly extaglia et al., 1995). pressed in the hypothalamus, a region of the brain Coleman and Eicher (1990) reported an autosomal involved in body weight regulation. Variation in the recessive mutation for obesity in mouse. This mutation, relative abundance of alternative splice products is called tubby (tub) arose spontaneously in a C57BL/6J observed between inbred mouse strains and appears colony. This is the only known allele of tub. Homozygous to correlate with an intron length polymorphism. This tub/tub mice, depending on sex and strain background, allele of tub is a candidate for a previously reported are recognizable by increased body weight at three to diet-induced obesity quantitative trait locus on mouse six months of age. Once the weight gain is apparent, it chromosome 7. is rapidly progressive and often results in animals that weigh twice as much as their littermate controls. Matu-Introduction rity-onset obesity is also characteristic of the fat mouse and is reminiscent of the pattern of weight gain com-Obesity (an abnormally high percentage of body fat relamonly observed in human populations. In contrast, tive to lean tissue mass) is strongly associated with a obese and diabetes mice begin rapid weight gain soon number of common diseases that have a major impact after birth. on morbidity and mortality including type II diabetes, Tubby mice develop insulin resistance with their hypertension, cardiovascular disease, hyperlipidaemia, weight gain but do not progress to overt diabetes. Conand some cancers (Grundy and Barnett, 1990). sistent with the absence of diabetes is the normal pa-Genetic approaches provide one strategy for defining thology observed in histological examination of a tubby the molecular components of the pathways involved in pancreas (Coleman and Eicher, 1990). In spite of the the regulation of body weight. In human populations, fact that the tubby obese phenotype is inherited in a the existence of a number of rare single-gene disorders recessive manner, some significant differences in lipid strongly associated with obesity, such as Bardet-Biedl profiles and susceptibility to atherosclerosis have been syndrome (Kwitek-Black et al., 1993) or the contiguous reported in tub heterozygotes (Nishina et al., 1994a, gene syndrome known as Prader-Willi syndrome (re-1994b). When fed an atherogenic diet, tub heterozygotes viewed in Knoll et al., 1993), suggests that genetic mechwere found to have significantly raised levels of plasma anisms can influence body weight. Susceptibility to obetriglycerides and a reduced susceptibility to aortic fatty sity in the general population appears to be a complex streak lesions, suggesting that there may be dominant trait, and a significant genetic component has been effects of the tub mutation. The influence of strain background on the susceptibility of tubby animals to diabetes, dyslipidemia, or atherosclerosis is unclear.
L'invention se rapporte a l'identification de nouvelles molecules d'acide nucleique e... more L'invention se rapporte a l'identification de nouvelles molecules d'acide nucleique et de proteines codees par ces dernieres ou leurs variants degeneres, qui sont actives dans le controle du poids corporel des mammiferes. Les molecules d'acide nucleique de l'invention representent les genes correspondant au gene tub mammifere, un gene qui est implique dans la regulation du poids du corps.
This paper applies objective methods to explore the technological origins of the widely acclaimed... more This paper applies objective methods to explore the technological origins of the widely acclaimed CRISPR breakthrough in the technological domain of genome engineering. Previously developed patent search techniques are first used to recover a set of patents that well-represent the genome editing domain before CRISPR. Main paths are then determined from the citation network associated with this patent set allowing identification of the three major knowledge trajectories. The most significant of these trajectories for CRISPR involves the core of genome editing with less significant trajectories involving cloning and endonuclease specific developments. The major patents on the core trajectory are consistent with qualitative expert knowledge of the topical area. A second set of patents that we call the CRISPR roots are obtained by finding the patents directly cited by the recent CRISPR patents along with patents cited by that set of patents. We find that the CRISPR roots contain 8 key p...
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation,... more In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
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Papers by Patrick Kleyn