- Bar Harbor, United States
Aamir Zuberi
The Jackson Laboratory, Genetic Resource Sciences, Department Member
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Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation... more
Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre–messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3′ splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2–dependent lysosome trafficking in TDP-43–deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.
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Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the... more
Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post‐translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre‐wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly identified patient‐based SUMF1 pathogenic variants, namely p.Ser153Pro and p.Ala277Val. These pathogenic missense variants correspond to variants detected in patients with attenuated MSD presenting with partial‐enzyme deficiency and relatively less severe disease. These novel MSD mouse model...
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The human mRNA most affected by TDP-43 loss-of-function is transcribed from theSTMN2gene and encodes stathmin-2 (also known as SCG10), whose loss is a neurodegenerative disease hallmark. Here using multiplein vivoapproaches, including... more
The human mRNA most affected by TDP-43 loss-of-function is transcribed from theSTMN2gene and encodes stathmin-2 (also known as SCG10), whose loss is a neurodegenerative disease hallmark. Here using multiplein vivoapproaches, including transient antisense oligonucleotide (ASO)-mediated suppression, chronic shRNA-mediated depletion in aging mice, and germline deletion, we establish stathmin-2 to be essential for acquisition and maintenance of neurofilament-dependent structuring of axoplasm critical for maintaining diameter and conduction velocity of large-myelinated axons. Sustained stathmin-2 loss from an otherwise mature adult nervous system is demonstrated over a time course of eight months to initiate and drive motor neuron disease that includes 1) shrinkage in inter-neurofilament spacing that is required to produce a three-dimensional space filling array that defines axonal caliber, 2) collapse of mature axonal caliber with tearing of outer myelin layers, 3) reduced conduction ve...
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Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in... more
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, while a fraction of patients are compound heterozygotes with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and in...
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Progranulin (PGRN) and transmembrane protein 106B (TMEM106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss‐of‐function mutations in progranulin (GRN)... more
Progranulin (PGRN) and transmembrane protein 106B (TMEM106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss‐of‐function mutations in progranulin (GRN) are a common cause of FTLD, while TMEM106B variants have been shown to act as disease modifiers in FTLD. Overexpression of TMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal and FTLD‐related pathologies in young Grn−/− mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD‐GRN. Here, we generate and characterize older Tmem106b−/−Grn−/− double knockout mice, which unexpectedly show severe motor deficits and spinal cord motor neuron and myelin loss, leading to paralysis and premature death at 11–12 months. Compared to Grn−/−, Tmem106b−/−Grn−/− mice have exacerbated FTLD‐related pathologies, including microgliosis, astrogliosis, ubiquitin, and phospho‐Tdp43 inclusions, as well as worsening of lysosomal and autophagic deficits. Our findings confirm a functional interaction between Tmem106b and Pgrn and underscore the need to rethink whether modulating TMEM106B levels is a viable therapeutic strategy.
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N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the... more
N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1-/- mouse cells demonstrated that NKCC1 has an altered average molecular weight and reduced function. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.
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Research Interests: Bacteriology, DNA, Motility, Methylation, Bacteria, and 4 moreSouthern Blotting, Chemotaxis, Genetic Mapping, and Locus
DNA-membrane association critical for initiation of DNA replication in Bacillus subtilis can be classified into two types. Type I is salt resistant and dependent on the initiation gene, dnaB, and type II is salt sensitive and independent... more
DNA-membrane association critical for initiation of DNA replication in Bacillus subtilis can be classified into two types. Type I is salt resistant and dependent on the initiation gene, dnaB, and type II is salt sensitive and independent of the dnaB gene. We found and sequenced two adjacent areas of type II binding within 1% of oriC on the B. subtilis chromosome.
Research Interests: Bacteriology, Kinetics, DNA replication, Biological Sciences, In Vitro, and 14 moreBacteria, Plasmids, Bacillus subtilis, Restriction Map, Gel electrophoresis, Amino Acid Sequence, Base Sequence, Plasmid, Molecular Sequence Data, Cell Membrane, Restriction Mapping, binding sites, Nucleotide sequence, and Medical and Health Sciences
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Research Interests: Information Systems, Genetics, Genomics, Polymorphism, Transcription Factors, and 17 moreComparative Study, Humans, Mice, Animals, Genetic Map, Transcription Factor, Genetic linkage analysis, High Resolution, High Density Concrete, Base Sequence, Graft Rejection, Thrombospondins, DNA binding proteins, Genetic Markers, Cytotoxic T cells, Genetic Linkage Map, and Molecular Sequence Data
Research Interests: Information Systems, Genetics, Genomics, Polymorphism, Transcription Factors, and 17 moreComparative Study, Humans, Mice, Animals, Genetic Map, Transcription Factor, Genetic linkage analysis, High Resolution, High Density Concrete, Base Sequence, Graft Rejection, Thrombospondins, DNA binding proteins, Genetic Markers, Cytotoxic T cells, Genetic Linkage Map, and Molecular Sequence Data
Research Interests: Obesity, Enzyme Inhibitors, Molecular endocrinology, Signal Transduction, Biological Sciences, and 18 moreMolecular, Insulin Resistance, Adipose tissue, Cell line, Glucose, Insulin, Mice, Animal Feed, Animals, Kinase inhibitor, Phosphorylation, Adipocytes, Fatty Acid, Free Fatty Acid, Glucose Uptake, Linoleic Acid, Insulin Receptor Substrate, and High fat diet
The classical minor histocompatibility 3 (H3) locus was originally defined by the phenotype of skin graft rejection, which is a complex genetic trait.H3is now known to be a gene complex comprised of a minimum of two functionally... more
The classical minor histocompatibility 3 (H3) locus was originally defined by the phenotype of skin graft rejection, which is a complex genetic trait.H3is now known to be a gene complex comprised of a minimum of two functionally interdependent alloantigen-encoding loci,H3aandH3b. H3aencodes a peptide recognized by cytotoxic T cells, andH3bencodes a peptide that stimulates helper T cells. TheH3complex also contains the β2-microglobulin gene (B2m), and polymorphisms inB2mcontribute to the tissue rejection phenotype. We describe a high-density genetic linkage map of a 16-cM region of mouse Chromosome 2 from thrombospondin (Thbs1) to paired box gene 1 (Pax1). This genetic map includesH3a, H3b,andB2m.Other genes and anonymous loci have also been placed on the map.H3amaps betweenD2Mit444andB2min close vicinity to several known genes.H3bmaps 12 cM distal toH3a,and the proprotein convertase subtilisin/kexin type 2 gene (Pcsk2;formerlyNec2) cosegregates withH3bin a high-resolution backcross panel. TheH3complex spans a region that shows conserved synteny to human chromosomes 15q, 2q, and 20p.
Research Interests: Information Systems, Genetics, Genomics, Polymorphism, Transcription Factors, and 17 moreComparative Study, Humans, Mice, Animals, Genetic Map, Transcription Factor, Genetic linkage analysis, High Resolution, High Density Concrete, Base Sequence, Graft Rejection, Thrombospondins, DNA binding proteins, Genetic Markers, Cytotoxic T cells, Genetic Linkage Map, and Molecular Sequence Data
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We have identified two peptides corresponding to the male-specific HY minor histocompatibility Ags presented by HLA-B27 in transgenic rodents, isolated from whole cell extracts and from immunoprecipitated B27 molecules of male B27 rat... more
We have identified two peptides corresponding to the male-specific HY minor histocompatibility Ags presented by HLA-B27 in transgenic rodents, isolated from whole cell extracts and from immunoprecipitated B27 molecules of male B27 rat spleen cells. HPLC peptide fractions that sensitized female B27 targets for lysis by B27-restricted anti-HY CTL were analyzed by electrospray tandem mass spectrometry using a new highly sensitive quadrupole/time-of-flight instrument. Two peptide sequences were obtained, KQYQKSTER and AVLNKSNREVR. Synthetic peptides corresponding to these sequences bound B27 in vitro and were recognized by distinct B27-restricted anti-HY CTL populations. Neither peptide sequence entirely matches known protein sequences or shows a resemblance to known Y chromosome genes, but both show homology to known autosomally encoded proteins. Both peptides were shown to be controlled by the Sxr(b) segment of the short arm of the mouse Y chromosome, a segment known to contain all previously identified HY Ags. Taken together, these findings suggest that the two peptides arise as a result of Y chromosome-regulated control of one or more autosomal gene products. Although arginine at position 2 is a dominant anchor residue for peptides bound to B27, neither B27-presented HY sequence contains this residue. These studies, employing sensitive new methodology for identification of MHC-bound peptides, significantly extend the complexity of the genetic basis of HY Ags and expand the repertoire of antigenically active peptides bound to B27.
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We have used Tn917lacZ to mutagenize the Bacillus subtilis chromosome and have isolated mutants that are defective in chemotaxis and motility. Mapping of the transposon inserts identified two new loci. Mutations in one of these loci... more
We have used Tn917lacZ to mutagenize the Bacillus subtilis chromosome and have isolated mutants that are defective in chemotaxis and motility. Mapping of the transposon inserts identified two new loci. Mutations in one of these loci generated mutants that had paralyzed flagella. Accordingly, we designate this a mot locus. The other locus is closely linked to the first and encodes proteins specifying chemotaxis functions. This locus is designated the cheX locus. Both the mot and cheX loci map close to ptsI. An additional transposon insert that maps in the hag locus was obtained. The pattern of beta-galactosidase expression from some of the transposons suggested that the mot locus is regulated by sigD, a minor sigma factor of B. subtilis. The cheX locus appeared to be under the control of vegetative sigA. Four transposon inserts were mapped to a previously characterized che locus near spcB. These mutants did not produce flagellin and were defective in the methylation of the methyl-accepting chemotaxis proteins. This locus probably encodes proteins required for flagellum biosynthesis and other proteins that are required for the methylation response.
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A cloned chemotaxis operon has been characterized. Thirteen representative che mutations from different complementation groups were localized on the physical map by recombination experiments. The use of integration plasmids established... more
A cloned chemotaxis operon has been characterized. Thirteen representative che mutations from different complementation groups were localized on the physical map by recombination experiments. The use of integration plasmids established that at least 10 of these complementation groups within this locus are cotranscribed. An additional three complementation groups may form part of the same transcript. The direction of transcription and the time of expression were determined from chromosomal che-lacZ gene fusions. The promoter was cloned and localized to a 3-kilobase fragment. Expression of beta-galactosidase from this promoter was observed primarily during the logarithmic phase of growth. Three-factor PBS1 cotransduction experiments were performed to order the che locus with respect to adjacent markers. The cheF141 mutation is 70 to 80% linked to pyrD1. This linkage is different from that reported previously (G. W. Ordal, D. O. Nettleton, and J. A. Hoch, J. Bacteriol. 154:1088-1097, 1983). The cheM127 mutation is 57% linked by transformation to spcB3. The gene order determined from all crosses is pyrD-cheF-cheM-spcB.
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Research Interests: Engineering, Humans, Insulin, American, Artemisia, and 3 moreAnthocyanins, Crassulaceae, and Time Factors
The gerA locus, mutations in which affect the germination response of spores to L-alanine and related amino acids, is contained within a 6-kilobase region of DNA cloned in phage and plasmid vectors. Fragments from this region, subcloned... more
The gerA locus, mutations in which affect the germination response of spores to L-alanine and related amino acids, is contained within a 6-kilobase region of DNA cloned in phage and plasmid vectors. Fragments from this region, subcloned in the shuttle vector pHV33, were introduced into Bacillus subtilis, and their ability to complement chromosomal gerA mutations in a recE4 background was examined. Although the plasmids were somewhat unstable, it was possible to score complementation within spore-containing colonies on nutrient agar by their ability to reduce 2,3,5-triphenyltetrazolium chloride in an overlay. These studies have assigned the 10 gerA mutations tested to three complementation groups. An analysis of Tn1000 insertions into the cloned DNA of two relatively stable plasmids that together encompass the entire gerA region has identified more precisely the location and extent of the complementation units; recombination studies and in vitro mutagenesis were used to further delin...
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Minor histocompatibility (H) Ags elicit T cell responses and thereby cause chronic graft rejection and graft-vs-host disease among MHC identical individuals. Although numerous independent H loci exist in mice of a given MHC haplotype,... more
Minor histocompatibility (H) Ags elicit T cell responses and thereby cause chronic graft rejection and graft-vs-host disease among MHC identical individuals. Although numerous independent H loci exist in mice of a given MHC haplotype, certain H Ags dominate the immune response and are thus of considerable conceptual and therapeutic importance. To identify these H Ags and their genes, lacZ-inducible CD8+ T cell hybrids were generated by immunizing C57BL/6 (B6) mice with MHC identical BALB.B spleen cells. The cDNA clones encoding the precursor for the antigenic peptide/Kb MHC class I complex were isolated by expression cloning using the BCZ39.84 T cell as a probe. The cDNAs defined a new H locus (termed H60), located on mouse chromosome 10, and encoded a novel protein that contains the naturally processed octapeptide LTFNYRNL (LYL8) presented by the Kb MHC molecule. Southern blot analysis revealed that the H60 locus was polymorphic among the BALB and the B6 strains. However, none of t...
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We have identified two peptides corresponding to the male-specific HY minor histocompatibility Ags presented by HLA-B27 in transgenic rodents, isolated from whole cell extracts and from immunoprecipitated B27 molecules of male B27 rat... more
We have identified two peptides corresponding to the male-specific HY minor histocompatibility Ags presented by HLA-B27 in transgenic rodents, isolated from whole cell extracts and from immunoprecipitated B27 molecules of male B27 rat spleen cells. HPLC peptide fractions that sensitized female B27 targets for lysis by B27-restricted anti-HY CTL were analyzed by electrospray tandem mass spectrometry using a new highly sensitive quadrupole/time-of-flight instrument. Two peptide sequences were obtained, KQYQKSTER and AVLNKSNREVR. Synthetic peptides corresponding to these sequences bound B27 in vitro and were recognized by distinct B27-restricted anti-HY CTL populations. Neither peptide sequence entirely matches known protein sequences or shows a resemblance to known Y chromosome genes, but both show homology to known autosomally encoded proteins. Both peptides were shown to be controlled by the Sxr(b) segment of the short arm of the mouse Y chromosome, a segment known to contain all pr...
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Research Interests: Pharmacokinetics, Pharmaceutics, Phytotherapy, Blood Glucose, Mice, and 14 moreAnimals, Male, Artemisia, Absorption, Bioavailability, High Pressure Liquid Chromatography, Intestinal absorption, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Plant extracts, Oral Hypoglycemic Agents, Extract, Experimental Diabetes Mellitus Type 1 and 2, Biological Availability, and Organic Chemicals
The present study investigated the inheritance of dietary fat, carbohydrate, and kilocalorie intake traits in an F(2) population derived from an intercross between C57BL/6J (fat-preferring) and CAST/EiJ (carbohydrate-preferring) mice.... more
The present study investigated the inheritance of dietary fat, carbohydrate, and kilocalorie intake traits in an F(2) population derived from an intercross between C57BL/6J (fat-preferring) and CAST/EiJ (carbohydrate-preferring) mice. Mice were phenotyped for self-selected food intake in a paradigm which provided for 10 days a choice between two macronutrient diets containing 78/22% of energy as a composite of either fat/protein or carbohydrate/protein. Quantitative trait locus (QTL) analysis identified six significant loci for macronutrient intake: three for fat intake on chromosomes (Chrs) 8 (Mnif1), 18 (Mnif2), and X (Mnif3), and three for carbohydrate intake on Chrs 17 (Mnic1), 6 (Mnic2), and X (Mnic3). An absence of interactions among these QTL suggests the existence of separate mechanisms controlling the intake of fat and carbohydrate. Two significant QTL for cumulative kilocalorie intake, adjusted for baseline body weight, were found on Chrs 17 (Kcal1) and 18 (Kcal2). Without...
Research Interests: Genetics, Obesity, Kinetics, Humans, Glucose, and 22 moreMice, Female, Animals, Male, Physiological, Medical Physiology, Feeding Behavior, Phenotype, Eating, Food intake, Dietary Carbohydrates, Quantitative Trait Loci, Body Weight, Dietary Protein, Energy Intake, Physiological Genomics, Cumulant, QTL analysis, Nutrient Intake, Dietary fat, Dietary fats, and Body Weight Gain
In this study, we investigated the metabolic phenotype of PKCtheta knockout mice (C57BL/6J) on chow diet and high-fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On the chow diet, body weight and food intake... more
In this study, we investigated the metabolic phenotype of PKCtheta knockout mice (C57BL/6J) on chow diet and high-fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On the chow diet, body weight and food intake were not changed in the KO mice; however, body fat content was increased with a corresponding decrease in body lean mass. Energy expenditure and spontaneous physical activity were decreased in the KO mice. On HFD, energy expenditure and physical activity remained low in the KO mice. The body weight and fat content were increased rapidly in the KO mice. At 8 wk on HFD, severe insulin resistance was detected in the KO mice with hyperinsulinemic euglycemic clamp and insulin tolerance test. Insulin action in both hepatic and peripheral tissues was reduced in the KO mice. Plamsa free fatty acid was increased, and expression of adiponectin in the adipose tissue was decreased, in the KO mice on HFD. This study suggests that loss of PKCtheta reduces energy ...
Research Interests: Obesity, Skeletal muscle biology, Physical Activity, Biological Sciences, Insulin Resistance, and 17 moreAdipose tissue, Glucose, Liver, Mice, Animals, Male, Energy Expenditure, Food intake, Adiponectin, Sensitivity, Isoenzymes, Body Weight, Body Fat, Protein Kinase, Knockout Mice, High fat diet, and Lean mass
Metabolic syndrome describes the human condition characterized by the presence of coexisting traditional risk factors for cardiovascular disease, such as hypertension, dyslipidemia, glucose intolerance, and obesity, in addition to... more
Metabolic syndrome describes the human condition characterized by the presence of coexisting traditional risk factors for cardiovascular disease, such as hypertension, dyslipidemia, glucose intolerance, and obesity, in addition to nontraditional cardiovascular disease risk factors, such as inflammatory processes and abnormalities of the blood coagulation system. Although the specific etiology for metabolic syndrome is not known, insulin resistance--a clinical state in which a normal or elevated insulin concentration reflects an impaired biological response--is present and is considered a key pathophysiologic abnormality. As such, metabolic syndrome can be considered to be a prediabetic state and contributes greatly to increased morbidity and mortality in humans. Given the public health significance of metabolic syndrome, successful strategies are direly needed to intervene in its development. As such, nutritional supplementation with botanicals that effectively address pathogenic me...
Research Interests: Engineering, Humans, Insulin, American, Artemisia, and 3 moreAnthocyanins, Crassulaceae, and Time Factors
The H3 complex, on mouse Chromosome 2, is an important model locus for understanding mechanisms underlying non-self Ag recognition during tissue transplantation rejection between MHC-matched mouse strains. H3a is a minor... more
The H3 complex, on mouse Chromosome 2, is an important model locus for understanding mechanisms underlying non-self Ag recognition during tissue transplantation rejection between MHC-matched mouse strains. H3a is a minor histocompatibility Ag gene, located within H3, that encodes a polymorphic peptide alloantigen recognized by cytolytic T cells. Other genes within the complex include beta2-microglobulin and H3b. A yeast artificial chromosome (YAC) contig is described that spans the interval between D2Mit444 and D2Mit17, a region known to contain H3a. This contig refines the position of many genes and anonymous loci. In addition, 23 new sequence-tagged sites are described that further increase the genetic resolution surrounding H3a. A novel assay was developed to determine the location of H3a within the contig. Representative YACs were modified by retrofitting with a mammalian selectable marker, and then introduced by spheroplast fusion into mouse L cells. YAC-containing L cells were...
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Metabolic syndrome,describes the human,condition characterized by the presence of coexisting traditional risk factors for cardiovas- cular disease, such as hypertension, dyslipidemia, glucose intoler- ance, and obesity, in addition to... more
Metabolic syndrome,describes the human,condition characterized by the presence of coexisting traditional risk factors for cardiovas- cular disease, such as hypertension, dyslipidemia, glucose intoler- ance, and obesity, in addition to nontraditional cardiovascular dis- ease risk factors, such as inflammatory processes and abnormalities of the blood coagulation system. Although the specific etiology for metabolic syndrome is not known, insulin resistance—a clinical state in which a normal or elevated insulin concentration reflects an impaired biological response—is present and is considered a key pathophysiologicabnormality.Assuch,metabolicsyndromecanbe considered to be a prediabetic state and contributes greatly to in- creased morbidity and mortality in humans. Given the public health significance of metabolic syndrome, successful strategies are direly needed to intervene in its development. As such, nutritional supple- mentationwithbotanicalsthateffectivelyaddresspathogenicmech- an...
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Research Interests: Obesity, Multidisciplinary, Adipose tissue, Association study, Gene Mapping, and 16 morePapio, Humans, Mutation, Mice, Animals, Animal Model, Body Mass Index, Phenotype, Genetic linkage analysis, Association, Quantitative Trait Loci, Body Weight, Genetic variation, Murine Model, Syndrome, and DNA sequence
Research Interests: Genetics, Polymorphism, Fluorescence Microscopy, Membrane Proteins, Signal Transduction, and 24 moreBiological Sciences, Cell line, Synapse, Insulin, Mutation, Mice, Animals, Retinal Degeneration, Insulin signaling, Animal Model, Protein structure, Hearing Loss, Proteins, Neurons, Phenotype, Molecular cloning, Protein Interaction, SYNAPSES, Quantitative Trait Loci, Gene Family, Protein Binding, Genetic Markers, Postsynaptic Density, and Immunoblotting
Research Interests: Obesity, Enzyme Inhibitors, Molecular endocrinology, Signal Transduction, Biological Sciences, and 18 moreMolecular, Insulin Resistance, Adipose tissue, Cell line, Glucose, Insulin, Mice, Animal Feed, Animals, Kinase inhibitor, Phosphorylation, Adipocytes, Fatty Acid, Free Fatty Acid, Glucose Uptake, Linoleic Acid, Insulin Receptor Substrate, and High fat diet
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Research Interests: Metabolism, Gene expression, Ghrelin, Blood Glucose, Insulin, and 23 moreMice, Animals, Body Composition, Male, Leptin, Animal Model, Eating, Clinical Sciences, Mouse Model, Digestive System, Fat Mass, Carbohydrate metabolism, Dietary fiber, Fat, Body Weight, Glucose Tolerance Test, Stomach, Area Under the Curve, Weight Gain, High fat diet, Dietary fats, Random Allocation, and Body Weight Gain
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Research Interests: Genetics, Physical Activity, Mice, Animals, Body Composition, and 16 moreEnergy Balance, Phenotype, Eating, Food intake, Phosphodiesterase Inhibitors, Skeletal Muscle, Microarray Analysis, Dietary Carbohydrates, Quantitative Trait Loci, Body Weight, New Physics, Energy Intake, Gene expression profiling, Nutrient Intake, Motor activity, and Dietary fat
Minor histocompatibility (H) loci are significant tissue transplantation barriers but are poorly understood at the genetic and molecular level. We describe the construction of a high-resolution genetic map that positions a class II... more
Minor histocompatibility (H) loci are significant tissue transplantation barriers but are poorly understood at the genetic and molecular level. We describe the construction of a high-resolution genetic map that positions a class II MHC-restricted minor H antigen locus and orders 12 other genes and genetic markers within the we-un interval of mouse Chromosome (Chr) 2. An intersubspecific backcross between B10.UW/Sn-H-3b and CAST/Ei, an inbred stock of Mus musculus castaneus, was used for this purpose. A total of 1168 backcross mice were generated, and 71 we-un recombinants were identified. Significant compression of the genetic map in males versus females and transmission distortion of CAST-derived we, un, and Aw genes were observed. Monoclonal T cell lines specific for two minor H alloantigens, Hd-1a and Hd-2a, encoded by gene(s) that map to the we-un interval were used to antigen type the backcross mice. The results suggest the Hd-1a and Hd-2a antigens are most likely encoded by a single gene, now referred to as H-3b. The determined gene order is we-0.09 +/- 0.09-Itp-0.62 +/- 0.23-D2Mit77-0.26 +/- 0.15-[Evi-4, Pcna, Prn-p]-0.26 +/- 0.15-Scg-1-0.44 +/- 0.19-[Bmp2a, D2Mit70]-0.09 +/-. 0.09-[D2Mit19, D2Mit46]-1.59 +/- 0.36-D2Mit28-0.97 +/- 0.28-D2Ler1-1.50 +/- 0.35-H-3b-0.26 +/- 0.15-un (% recombination +/- 1 SE). Because the average resolution of the backcross is 0.09 cM, the backcross panel should facilitate the physical mapping and molecular identification of a number of genes in this chromosome region.
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An ethanolic extract of Artemisia dracunculus L. (PMI 5011) has been observed to decrease glucose and insulin levels in animal models, but the cellular mechanisms by which insulin action is enhanced in vivo are not precisely known. In... more
An ethanolic extract of Artemisia dracunculus L. (PMI 5011) has been observed to decrease glucose and insulin levels in animal models, but the cellular mechanisms by which insulin action is enhanced in vivo are not precisely known. In this study, we evaluated the effects of PMI 5011 to modulate gene expression and cellular signaling through the insulin receptor in skeletal muscle of KK-A(y) mice. Eighteen male KK-A(y) mice were randomized to a diet (w/w) mixed with PMI 5011 (1%) or diet alone for 8 weeks. Food intake, adiposity, glucose and insulin were assessed over the study, and at study completion, vastus lateralis muscle was obtained to assess insulin signaling parameters and gene expression. Animals randomized to PMI 5011 were shown to have enhanced insulin sensitivity and increased insulin receptor signaling, i.e., IRS-associated PI-3 kinase activity, Akt-1 activity and Akt phosphorylation, in skeletal muscle when compared to control animals (P<.01, P<.01 and P<.001, respectively). Gene expression for insulin signaling proteins, i.e., IRS-1, PI-3 kinase and Glut-4, was not increased, although a relative increase in protein abundance was noted with PMI 5011 treatment. Gene expression for specific ubiquitin proteins and specific 20S proteasome activity, in addition to skeletal muscle phosphatase activity, i.e., PTP1B activity, was significantly decreased in mice randomized to PMI 5011 relative to control. Thus, the data demonstrate that PMI 5011 increases insulin sensitivity and enhances insulin receptor signaling in an animal model of insulin resistance. PMI 5011 may modulate skeletal muscle protein degradation and phosphatase activity as a possible mode of action.
Research Interests: Nutrition and Dietetics, Nutrition, Skeletal muscle biology, Gene expression, Signal Transduction, and 25 moreInsulin Resistance, Phytotherapy, Insulin, Muscle, Mice, Animals, Male, Insulin signaling, Animal Model, Dietary Supplements, Artemisia, Food intake, Nutritional Biochemistry, Mode of action, Plant extracts, Skeletal Muscle, Oral Hypoglycemic Agents, Protein Degradation, Food Sciences, Insulin Receptor, Extract, Biochemistry and cell biology, Gene Expression Regulation, Gene expression profiling, and Random Allocation
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The purpose of this study was to elucidate the genetic origin of minor histocompatibility (H) antigens. Toward this end common inbred mouse strains, distinct subspecies, and species of the subgenus Mus were examined for expression of... more
The purpose of this study was to elucidate the genetic origin of minor histocompatibility (H) antigens. Toward this end common inbred mouse strains, distinct subspecies, and species of the subgenus Mus were examined for expression of various minor H antigens. These antigens were encoded by the classical minor H loci H-3 and H-4 or by newly identified minor H antigens detected as a consequence of mutation. Both minor H antigens that stimulate MHC class I-restricted cytotoxic T cells (Tc) and antigens that stimulate MHC class II-restricted helper T cells (Th) were monitored. The results suggested that strains of distinct ancestry commonly express identical or cross-reactive antigens. Moreover, a correlation between the lack of expression of minor H antigens and ancestral heritage was observed. To address whether the antigens found on unrelated strains were allelic with the sensitizing minor H antigens or a consequence of antigen cross-reactivity, classical genetic segregation analysis was carried out. Even in distinct subspecies and species, the minor H antigens always mapped to the site of the appropriate minor H locus. Together the results suggest: 1) minor H antigen sequences are evolutionarily stable in that their pace of antigenic change is slow enough to predate subspeciation and speciation; 2) the minor H antigens originated in the inbred strains as a consequence of a rare polymorphism or loss mutation carried in a founder mouse stock that caused the mouse to perceive the wild-type protein as foreign; 3) there is a remarkable lack of antigenic cross-reactivity between the defined minor H antigens and other gene products.
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The products of minor histocompatibility (H) loci are serious barriers to tissue transplantation even among major histocompatibility complex (MHC) identical individuals, frequently causing chronic graft rejection and graft versus host... more
The products of minor histocompatibility (H) loci are serious barriers to tissue transplantation even among major histocompatibility complex (MHC) identical individuals, frequently causing chronic graft rejection and graft versus host disease. Over 50 minor H loci map to mouse autosomal chromosomes but none are known at the molecular level. By expression cloning, we identified the H13 locus, a classical minor H locus first detected 30 years ago by the trait of graft rejection. The H13a allele is located on chromosome 2 and encodes a novel protein that yields the rare naturally processed nonapeptide SSVVGVWYL (SVL9) for presentation by the Db MHC class I molecule. The SVL9 peptide binds Db MHC despite the absence of the consensus binding motif, and a conservative methyl group substitution (Valine 4 <--> Isoleucine) explains why reciprocal T cell responses are elicited in H13a and H13b congenic strains.
Research Interests: Genetics, Immunology, Polymorphism, Mice, Immunity, and 14 moreAnimals, Epitope mapping, Peptides, Molecular cloning, Hybrid Solar Cells, Major histocompatibility complex, Amino Acid Sequence, Base Sequence, Graft Rejection, Amino Acid Substitution Rates, MHC class I, Graft-Versus-Host Disease, Minor Histocompatibility Antigens, and Molecular Sequence Data
... Plasmids expressing Zfp106 minigenes were tested for the ability to encode H3a a in H2-D b transfected COS cells (Figure 4A ... The same 5′ primer (designated START 2) containing a nonnative AUG in-phase codon was used to initiate... more
... Plasmids expressing Zfp106 minigenes were tested for the ability to encode H3a a in H2-D b transfected COS cells (Figure 4A ... The same 5′ primer (designated START 2) containing a nonnative AUG in-phase codon was used to initiate translation in both minigene constructs. ...
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Research Interests: Genetics, Biological Sciences, Hearing disorders, Mice, Animals, and 14 moreHuman Molecular Genetics, Genetic modification, Retinal Degeneration, Hearing Loss, Proteins, Genetic linkage analysis, Fluorescent Antibody Technique, Genotype, Quantitative Trait Loci, Auditory Brainstem Response, Complex Traits, Cochlea, QTL analysis, and Brain stem
Research Interests: Information Systems, Genetics, Genomics, Polymorphism, Transcription Factors, and 17 moreComparative Study, Humans, Mice, Animals, Genetic Map, Transcription Factor, Genetic linkage analysis, High Resolution, High Density Concrete, Base Sequence, Graft Rejection, Thrombospondins, DNA binding proteins, Genetic Markers, Cytotoxic T cells, Genetic Linkage Map, and Molecular Sequence Data
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The nucleotide sequence of the second and third genes in the Bacillus subtilis spore germination locus, gerA, has been determined and the amino acid (aa) sequence was derived. Two open reading frames (ORFs), corresponding to genes II and... more
The nucleotide sequence of the second and third genes in the Bacillus subtilis spore germination locus, gerA, has been determined and the amino acid (aa) sequence was derived. Two open reading frames (ORFs), corresponding to genes II and III, encode 364-aa residue and 373-aa residue polypeptides, respectively. The gene II product, Mr 41,257, would contain long stretches of hydrophobic aa residues and may be a membrane protein; the gene III product, Mr 42,363, is relatively hydrophilic but possesses an apparent signal peptide for transfer across, and perhaps localisation on, a membrane. The ORFs for genes I and II overlap by eleven codons and the termination codon of gene II overlaps the initiation codon of gene III. Insertional inactivation experiments using integrational plasmids have indicated that the gerA locus is a single transcriptional unit. The expression of the gerA genes has been studied using a lacZ transcriptional fusion; they constitute a developmentally regulated operon.
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The nucleotide sequence of five genes from the major Bacillus subtilis chemotaxis locus has been determined. Four of these genes encode proteins that are homologous to the Salmonella typhimurium FlgB, FlgC, FlgG and FliF proteins. One... more
The nucleotide sequence of five genes from the major Bacillus subtilis chemotaxis locus has been determined. Four of these genes encode proteins that are homologous to the Salmonella typhimurium FlgB, FlgC, FlgG and FliF proteins. One gene encodes a protein that is homologous to the Escherichia coli FliE protein. The data from S. typhimurium and E. coli suggest that all of these proteins form part of the hook-basal body (HBB) complex of the bacterial flagella. The FlgB, FlgC and FlgG proteins are components of the proximal and distal rods. The FliF protein forms the M-ring that anchors the rod assembly to the membrane. The role of the FliE protein within the HBB complex has not yet been determined. The similarity between the B. subtilis and S. typhimurium proteins suggests that the structure of the M-ring and the rod may be similar in the two species. However, we observed some differences in size and amino acid composition between some of the corresponding homologues that suggest the basal body proteins may be organized slightly differently within B. subtilis.
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The amino acid sequences of the Bacillus subtilis flagellar proteins, FliP, FliQ, FliR and FlhB, as deduced from their respective nucleotide sequences, were found to share significant homology to the Shigella flexneri Spa24, Spa9, Spa29... more
The amino acid sequences of the Bacillus subtilis flagellar proteins, FliP, FliQ, FliR and FlhB, as deduced from their respective nucleotide sequences, were found to share significant homology to the Shigella flexneri Spa24, Spa9, Spa29 and Spa40 virulence proteins, respectively. These proteins are required for the presentation of surface plasmid antigens. These results further support the growing hypothesis that a superfamily of proteins exists for the biosynthesis of supramolecular structures that lie in an external to the cell membrane.
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Harlequin ichthyosis (HI) is a rare and usually fatal scaling skin disorder. The HI mutant mouse (ichq/ichq) has many similarities to the human disorder and provides an important model to identify candidate genes. In this study, we report... more
Harlequin ichthyosis (HI) is a rare and usually fatal scaling skin disorder. The HI mutant mouse (ichq/ichq) has many similarities to the human disorder and provides an important model to identify candidate genes. In this study, we report refined mapping of the mouse ichq locus and consideration of the candidate genes: calpain 1 (Capn1), phospholipase C beta 3 (Plcb3), and Rela and Ikka/Chuk that encode components of the nuclear factor-kappa B (NF-kappaB) pathway. Each are strong candidates because of epidermal expression and/or changes in expression in human HI. All candidates are linked to the ichq locus on mouse Chromosome 19, although Ikka is located more distally. Genetic mapping in mouse has narrowed the ichq critical region to 4 cM. Keratinocytes from skin of +/+, +/ichq and ichq/ichq mice were cultured; all genotypes had similar expression of epidermal differentiation markers. RT-PCR amplification and sequence analysis of each candidate gene did not reveal any mutations in the ichq mouse. Mutational screening of CAPN1 cDNA from different human HI cases revealed a R433P change, but analysis of 50 normal samples demonstrated that this was an apparent polymorphism. Sequence of RELA in five unrelated human HI cases was normal. The results provide compelling evidence that none of these genes are the primary defect in the ichq mouse and that CAPN1 and RELA are not mutated in the human disorder.
Research Interests: Polymorphism, Gene expression, Sequence Analysis, Cell Culture, Cell Differentiation, and 17 moreHumans, Keratinocytes, Mice, Animals, NF-kappa B, Genetic Map, Pedigree, Epidermis, Clinical Sciences, Calpain, Experimental, Amino Acid Sequence, Cytoplasm, Genetic Markers, nuclear factor kappa B, Phospholipase C, and Molecular Sequence Data
Research Interests: Genetics, Obesity, Gene regulation, Disease susceptibility, Adipose tissue, and 19 moreGlucose, Mice, Female, Animals, Body Composition, Male, Mu Opioid Receptor, Food intake, European, Fat Mass, Sex Factors, Body Weight, Glucose Tolerance Test, Opioid Receptor, Reference Value, Endorphins, Energy Intake, High fat diet, and Dietary fats
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Minor histocompatibility (H) antigens were first defined at the cellular level approximately 50 years ago. Since then, over 50 distinct H loci have been identified based upon their inheritance and segregation patterns in recombinant and... more
Minor histocompatibility (H) antigens were first defined at the cellular level approximately 50 years ago. Since then, over 50 distinct H loci have been identified based upon their inheritance and segregation patterns in recombinant and congenic mouse strains. Polymorphisms in ...