Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory
600 Main St
bar Harbor, Me 046091500
Grant 2T32HD007065-21 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development IRG: ZHD1
Abstract: The Jackson Laboratory (TJL) requests funding for continuation of its postdoctoral research training program in developmental genetics. Twelve members of the TJL Research staff form an interdisciplinary pool of trainee mentors. The major research training theme are the regulation of gene expression and the role of intercellular signaling in developmental decisions in mice. Another important goal of this program is training in the use of the laboratory mouse as an experimental system for the study of human development, birth defects and disease. Support is requested for four trainees. Candidates must be recent recipients of the doctoral degree (usually but not limited to the Ph.D. with 0-3 years of previous postdoctoral training). Each trainee is sponsored by a TJL faculty member in a program tailored to the trainee´s individual needs and the sponsor´s interests. Trainees devoted their major effort to bench research, and also are integrated into TJL seminars, short courses, workshops, and research interest groups. All trainees are required to apply for independent funding during their first year in the program, and to regularly present their work at the TJL Interest Groups and at national or international meetings. Upon completion of training, participants will be qualified to engage in creative, independent research in developmental genetics at a university, research institution, or in the biotechnology or pharmaceutical industry. The primary training facility is TJL, a private, independent research center. TJL is an NCI Cancer Research Center, distributes 3 million genetically standardized mice annually, and has held NIH research training grants continuously since 1956. During the past five years, TJL as added a new 49,000 square foot research building, 15 new members have joined the research Staff, numerous modern scientific services (e.g., Induced Mutant Resource) have been added, postdoctoral enrollment has more than doubled, and construction has begun on a new Genetics Resources Building
Project start date: 1977-07-01
Project end date: 2004-04-30
2T32HD007065-21 (1999): $118798
Sponsored Links Excellgen http://Excellgen.com
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory, 600 Main St, Bar Harbor, Me 04609-1500
Grant 2T32HD007065-31A1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This renewal application requests continued support for our postdoctoral training program in developmental genetics at The Jackson Laboratory (TJL). A primary theme of this training program, which was first funded in 1977, is use of the laboratory mouse as a model system for the study of human development, birth defects and disease. Sixteen TJL faculty members participate as mentors in this program. Research training areas include germ cell development, postimplantation embryonic development, neural and motor neuron development, epilepsy models, computational and systems biology, complex trait analysis, eye development and disease, control of genome stability, the relationship between gene expression and three-dimensional chromosome structure in the nucleus, and the developmental regulation of homeostatic mechanisms. These analyses are made possible by the availability of TJL´s unparalleled resource base of more than 4,100 inbred, spontaneous and genetically-engineered mutant mice. Support is requested for three postdoctoral trainees. Trainees devote their major effort to laboratory research, but also receive training in scientific integrity, presentation skills, data analysis and grant writing. Trainees participate in TJL seminars, courses, workshops, and research interest groups. They are required to write fellowship applications, and present their results both at in-house interest groups and at national and international meetings. Their progress is overseen by a formal Training Committee, which evaluates new candidates for the program and monitors progress of the trainees annually. Each member of the Training Committee also acts as an informal mentor, or liaison, for several postdoctoral trainees at TJL. Upon completion of training, program participants are qualified to engage in creative, independent research in developmental genetics at a university, research institution, or in industry
Keywords: developmental genetics
Project start date: 1977-07-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-08-226
2T32HD007065-31A1 (2010): $23489
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 2T32HD007065-26 from National Institute Of Child Health And Human Development IRG: CHHD
Abstract: Researchers at The Jackson Laboratory have a long and successful track record in training a cadre of research scientists in the complexity of regulation of gene expression and the role of intercellular signaling in developmental decisions in mice. This philosophy, an integral part of the Laboratory s strategic plan, has dictated the ongoing expansion of the overall training program at The Jackson Laboratory, which requests funding for continuation of its well-established postdoctoral research training program in developmental genetics. Fourteen members of The Jackson Laboratory Research Staff form an interdisciplinary pool of trainee preceptors who are investigating pre-implantation and post-implantation embryonic development, germ cell differentiation, eye development, primary sex determination, and the developmental regulation of homeostatic mechanisms in adult animals. These types of analyses are made possible by the availability of the Laboratory s unparalleled resource base of special inbred, spontaneous and induced-mutant mice, and curated knowledge about them. Support is requested for four trainees, who will devote their major effort to bench research, and are integrated into The Laboratory s seminars, courses, workshops, and research interest groups. They are required to write fellowship applications, and present their results both at in-house interest groups and international meetings. Their progress is overseen by a formal Training Committee, in which each member acts as an informal mentor, or liaison, for several trainees. Upon completion of training, participants will be qualified to engage in creative, independent research in developmental genetics at a university, research institution, or in industry. The continued quality of the program is evidenced in part by the fact that eight of the twelve trainees supported by this program in the last reporting period obtained independent fellowships. The primary training facility IS TJL, a private, independent research center. TJL is an NCI-designated Cancer Center, with a research budget of $53.9 million, raises 3 million mice annually, and has held NIH research training grants continuously since 1956.
Project start date: 1977-07-01
Project end date: 2009-04-30
2T32HD007065-26 (2004): $107245
Grants awarded to Thomas H Gridley
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory, 600 Main St, Bar Harbor, Me 04609-1500
Abstract: The mission of the Cell Biology & Microinjection component of Reproductive Sciences is to provide Cancer Center members with access to centralized facilities, instrumentation and technical expertise necessary to allow investigators to carry out embryonic stem (ES) cell line derivation, electroporation, and to create genetically modified mice for in vivo studies of gene function. The Service generates genetically modified mice on a variety of inbred strain and hybrid backgrounds and has derived germline-competent ES cell lines from inbred mouse strains. Germline-competence validation, training, custom projects, and tested reagents and supplies are also offered. The Service, which has previously been supported by Cancer Center support grant (CCSG) funds, works closely with Cryopreservation, Importation and Rederivation within Reproductive Sciences, as well as Phenotyping Sciences to provide Cancer Center members well integrated comprehensive services. In 2004 the Cell Biology & Microinjection Service merged with the Reproductive Technologies Resource to form Reproductive Sciences. The synergy created by the merger allowed management and staff to identify complementary and overlapping functions within the groups; establish new collaborative service offerings; merge similar processes to eliminate redundancy; and combine laboratory, vivarium and office space to maximize productivity. Cell Biology & Microinjection Service personnel work closely with other members of Reproductive Sciences and the Molecular Biology Service to offer Cancer Center investigators seamless access to services. This close internal collaboration insures that investigators with expertise outside of these areas can fully employ current transgenic and gene targeting technology in their own work by utilizing these interactive services. Senior Staff Scientist Dr. Thomas Gridley was named Faculty Advisor (Project Leader) of Cell Biology & Microinjection Service in 1999. He oversees this fee-for-service operation which employs two ES cell technologists, two microinjection technologists, a colony manager and senior operational manager. The Service occupies 1,899 ft2 of laboratory, vivarium and office space in Research Laboratory Building 4 and the Genetics Resources Building. Dr. Gridley communicates with the Cancer Center users, Service staff and Center Administration to ensure that research needs are met in the most efficient, cost-effective and technically current manner
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5P30CA034196-27_9004 (2010): $227845
5P30CA034196-26_9004 (2009): $244482
Genetic Analysis Of Snail Superfamily Genes In Mice
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 2R01HD034883-06 from National Institute Of Child Health And Human Development IRG: CDF
Abstract: The long-term goal of this proposal is to understand the roles that Snail superfamily genes play during embryonic development in mammals. Snail superfamily genes encode zinc finger-containing DNA binding proteins that act as transcriptional repressors. This superfamily has two main branches the Snail family and the Scratch family. Each branch of the Snail superfamily in vertebrates has two members Snail and Slug for the Snail family, and Seratchl and Scratch2 for the Scratch family. We have been studying the Snail gene family members Sna and Slug, and have constructed and analyzed targeted null mutations of both of these genes. Sna homozygous mutant embryos die during gastrulation, exhibiting defects in the epithelialmesenchymal transition required for generation of the mesoderm. Slug homozygous mutant mice are viable, but show growth retardation and various other defects. However, many questions remain about the possible roles played by the Sna gene in developmental events occurring after gastrulation, or whether the Snail superfamily genes Scratchl and Scratch2 play essential roles during embryogenesis. In this proposal, both molecular and genetic approaches will be utilized to examine the roles that Snail superfamily genes play during embryogenesis in mice. The specific aims of this proposal are 1) Construct conditional loss and gain of function alleles of the Sna gene to analyze its role during postgastrulation developmental stages; 2) Test the hypothesis that the roles of the vertebrate Snail and Slug genes have been interchanged during evolution from fish, amphibians and birds to mammals by constructing a knock-in allele of the Slug cDNA into the Sna locus; 3) Construct and analyze targeted null mutations of the Snail superfamily genes Scratch1 and Scratch2; 4) Examine the role of the Sna gene in development of the trophoblast cell lineage; 5) Identify downstream transcriptional targets of the Sna protein using microarray analysis of Sna mutant cell lines and embryos, in silico analysis of DNA binding sites, and DNA binding studies. These studies will further our understanding of the roles played by Snail superfamily genes during mammalian development, and will be relevant to the study of both normal and abnormal human development.
Keywords: cell migration, early embryonic stage, embryogenesis, epithelium, gene expression, genetic regulation, mesoderm, neural crest, DNA binding protein, cell growth regulation, developmental genetics, gene mutation, transcription factor, chimeric protein, comparative genomic hybridization, computer assisted sequence analysis, electroporation, fluorescent dye /probe, gene targeting, immunocytochemistry, laboratory mouse, microarray technology, molecular cloning, polymerase chain reaction, southern blotting, tissue /cell culture
Project start date: 1998-01-01
Project end date: 2007-12-31
2R01HD034883-06 (2003): $366750
Genetic Analysis Of The Notch Signaling Pathway
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 5R01NS036437-12 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: The long-term goal of this proposal is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals, and the connections between this pathway and the development of congenital human disease syndromes. The components of the Notch signaling pathway are essential for proper embryonic development in numerous organisms, and mutations in Notch pathway genes cause several inherited human disease syndromes. In mammals, four Notch family receptors have been described, encoded by the Notch1 - Notch4 genes. Notch receptors interact with membrane-bound ligands that are encoded by the Jagged (Jag1 and Jag2) and Delta-like (Dlll, Dll3, and Dll4) gene families. We have been performing a comprehensive genetic analysis of the requirements for Notch pathway components during embryonic development in mice. The aims of this proposal are to 1) determine the role of the Dll4 gene and of other Notch pathway components in the development of the cardiovascular system; 2) test whether the PDZ Iigand domains at the carboxy termini of the JAG1 and DLL4 proteins are essential for function; 3) test whether the intracellular domains of the four different Notch receptors transmit equivalent signals by constructing single copy conditional gain of function alleles at the same genetic locus; 4) test whether Notch signaling plays an evolutionarily-conserved role during oocyte development. These studies will further our understanding of the roles of the Notch signaling pathway in mammalian development, and will be applicable to the study of both normal development and birth defects in humans.
Keywords: biological signal transduction, cell surface receptor, developmental genetics, mammalian embryology, allele, cardiac myocyte, cardiogenesis, cell differentiation, egg /ovum, gene interaction, gene mutation, genetic regulatory element, phenotype, receptor expression, vascular smooth muscle, embryonic stem cell, gene targeting, genetically modified animal, laboratory mouse, mutant, tissue /cell culture, tissue mosaicism, yeast two hybrid system
Project start date: 1996-09-09
Project end date: 2008-06-30
5R01NS036437-12 (2007): $450201
5R01NS036437-11 (2006): $450137
5R01NS036437-10 (2005): $447546
2R01NS036437-09 (2004): $434511
5R01NS036437-08 (2003): $352290
5R01NS036437-07 (2002): $342029
5R01NS036437-06 (2001): $332069
Sponsored Links Excellgen http://Excellgen.com
5R01NS036437-05 (2000): $322397
2R01NS036437-04 (1999): $313007
GENETIC CONTROL OF MESODERM AND NEURAL CREST FORMATION
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory
600 Main St
bar Harbor, Me 046091500
Grant 5R01HD034883-04 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development IRG: HED
Abstract: The long term goal of this proposal is to understand the molecular and genetic mechanisms that regulate cell migration and epithelial-mesenchymal transitions in early postimplantation mouse embryos. In this proposal, these questions will be studied by constructing and analyzing targeted null mutations of the genes sna and slug. These genes are mouse homologs of the Drosophila gene snail, which encodes a zinc finger protein that is required zygotically for mesoderm formation during Drosophila embryogenesis. Analysis of snail homologs in other vertebrates suggests that snail family genes are important in regulating adhesive interactions between cells, such as the interactions involved in the epithelial-mesenchymal transition required for the generation of both the mesoderm and the neural crest. The specific aims of this proposal are 1) Test the hypothesis that the sna and slug genes are essential for normal embryonic development, and that embryos homozygous for null mutations of these genes will show defects in delamination and migration of tissues such as mesoderm, parietal endoderm and neural crest, by generating and characterizing mice containing null mutations in these genes. 2) Assess the cell autonomy of sna and slug mutant phenotypes by constructing embryonic stem cell lines homozygous for sna and slug mutant alleles, and analyzing the behavior of these cells in chimeric embryos. 3) Determine whether the sna and slug genes in mice are in part functionally redundant by constructing and analyzing sna/slug double mutants. 4) Determine the DNA binding site specificity of recombinant SNA and SLUG proteins, and generate antibodies specific for these proteins. 5) Clone additional members of the snail gene family, and characterize their expression in both wild type embryos and in sna and slug mutant embryos
Keywords: cell migration, early embryonic stage, embryogenesis, epithelium, gene expression, genetic regulation, mesoderm, neural crest DNA binding protein, cell growth regulation, developmental genetics, gene mutation, transcription factor chimeric protein, computer assisted sequence analysis, embryonic stem cell, gene targeting, hybrid cell, immunocytochemistry, immunofluorescence technique, in situ hybridization, laboratory mouse, molecular cloning, polymerase chain reaction, tissue /cell culture
Project start date: 1998-01-01
Project end date: 2002-12-31
5R01HD034883-04 (2001): $285038
5R01HD034883-03 (2000): $271166
5R01HD034883-02 (1999): $258012
1R01HD034883-01A1 (1998): $245540
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 5T32HD007065-25 from National Institute Of Child Health And Human Development IRG: ZHD1
Abstract: The Jackson Laboratory (TJL) requests funding for continuation of its postdoctoral research training program in developmental genetics. Twelve members of the TJL Research staff form an interdisciplinary pool of trainee mentors. The major research training theme are the regulation of gene expression and the role of intercellular signaling in developmental decisions in mice. Another important goal of this program is training in the use of the laboratory mouse as an experimental system for the study of human development, birth defects and disease. Support is requested for four trainees. Candidates must be recent recipients of the doctoral degree (usually but not limited to the Ph.D. with 0-3 years of previous postdoctoral training). Each trainee is sponsored by a TJL faculty member in a program tailored to the trainee s individual needs and the sponsor s interests. Trainees devoted their major effort to bench research, and also are integrated into TJL seminars, short courses, workshops, and research interest groups. All trainees are required to apply for independent funding during their first year in the program, and to regularly present their work at the TJL Interest Groups and at national or international meetings. Upon completion of training, participants will be qualified to engage in creative, independent research in developmental genetics at a university, research institution, or in the biotechnology or pharmaceutical industry. The primary training facility is TJL, a private, independent research center. TJL is an NCI Cancer Research Center, distributes 3 million genetically standardized mice annually, and has held NIH research training grants continuously since 1956. During the past five years, TJL as added a new 49,000 square foot research building, 15 new members have joined the research Staff, numerous modern scientific services (e.g., Induced Mutant Resource) have been added, postdoctoral enrollment has more than doubled, and construction has begun on a new Genetics Resources Building.
Project start date: 1977-07-01
Project end date: 2004-04-30
5T32HD007065-25 (2003): $205736
5T32HD007065-23 (2001): $101275
5T32HD007065-22 (2000): $101696
GENETIC ANALYSIS OF SNAIL SUPERFAMILY GENES IN MICE
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory, 600 Main St, Bar Harbor, Me 04609-1500
Grant 5R01HD034883-13 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Snail superfamily genes encode zinc finger-containing DNA binding proteins that act as transcriptional repressors. This superfamily has two main branches the Snail family (encoded by the Snai1, 2 and 3 genes) and the Scratch family (the Scrt1 and 2 genes). These proteins are key regulators of the epithelial- mesenchymal transition, and also play roles in cell proliferation, survival and movement. We have performed a comprehensive genetic analysis of the requirements for Snail superfamily genes during embryonic development in mice. Our work during the prior funding periods of this grant established the null phenotype of all of these genes, and demonstrated that the most severe embryonic phenotype is observed in Snai1 mutants. However, many questions remain about the requirements and roles of Snail superfamily genes. In this proposal, both molecular and genetic approaches will be utilized to analyze the roles played by Snail family genes during embryogenesis in mice, and to understand the mechanisms causing the mutant phenotypes. The mutant mouse strains we have already generated, as well as the mutant strains we will construct as part of this proposal, constitute a unique set of reagents that will permit us to finely dissect the roles of Snail family genes during embryonic development. The specific aims of this proposal are 1) determine targets for transcriptional repression by the SNAI1 protein during early embryogenesis in mice; 2) test the hypothesis that post- translational regulation of SNAI1 protein by the GSK3beta kinase and the betaTrcp ubiquitin ligase are essential for Snai1 function in vivo; 3) test the hypothesis that Snail family genes are important for muscle development, physiology and regeneration by determining the individual roles of the Snai1, Snai2 and Snai3 genes in these processes; 4) assess Snai3 redundancy with Snai2 and Snai1 function during muscle development, physiology and regeneration. The long-term goal of this proposal is to understand the roles that Snail superfamily genes play during embryonic development in mammals. Snail superfamily genes encode zinc finger-containing DNA binding proteins that act as transcriptional repressors. The studies described in this proposal will further our understanding of the roles played by Snail superfamily genes during mammalian development, and will be relevant to the study of both normal and abnormal human development
Keywords: 20S Catalytic Proteasome; 20S Core Proteasome; 20S Proteasome; 20S Proteosome; Alleles; Allelomorphs; Amino Acid Motifs; Amino Acids, Essential; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cells; Cellular Proliferation; DNA-Binding Proteins; Development; EC 2.7; Embryo; Embryo Development; Embryogenesis; Embryonic; Embryonic Development; Epithelial; Essential Amino Acids; Family; Funding; Gene Down-Regulation; Gene Family; Gene Targeting; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic analyses; Genetic defect; Goals; Grant; Homozygote; Human Development; Individual; Kinases; Knock-in; Knock-in Mouse; Left; Macropain; Macroxyproteinase; Mammalia; Mammals; Mammals, General; Mammals, Mice; Mediating; Mesenchymal; Mice; Mice, Mutant Strains; Molecular Genetic; Molecular Genetics; Movement; Multicatalytic Proteinase; Murine; Mus; Muscle Development; Muscle, Skeletal; Muscle, Voluntary; Muscular Development; Mutant Strains Mice; Mutate; Mutation; Natural regeneration; Nuclear; Phenotype; Phosphorylation; Phosphotransferases; Physiology; Play; Post-Translational Modifications; Post-Translational Protein Processing; Post-Translational Regulation; Posttranslational Modifications; Posttranslational Regulation; Process; Prosome; Proteasome; Proteasome Endopeptidase Complex; Protein Family; Protein Modification; Protein Modification, Post-Translational; Protein Motifs; Protein Phosphorylation; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proteosome; Reagent; Regeneration; Role; Skeletal Muscle Tissue; Skeletal muscle structure; Snails; Staging; Targetings, Gene; Testing; Transcription Corepressor; Transcription Repression; Transcription Repressor; Transcription Repressor/Corepressor; Transcriptional Corepressor; Transcriptional Repression; Transcriptional Repressor; Transcriptional Repressor/Corepressor; Transphosphorylases; Work; Zinc Finger Domain; Zinc Finger Motifs; Zinc Fingers; beta-TrCP; beta-Transducin Repeat-Containing Proteins; betaTrCP; body movement; essential amino acid; essential aminoacid; gastrulation; gene product; gene repression; genetic analysis; genome mutation; in vivo; mouse mutant; multicatalytic endopeptidase complex; muscle regeneration; mutant; public health relevance; regenerate; social role; ubiquitin ligase
Project start date: 1998-01-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
5R01HD034883-13 (2010): $366053
Sponsored Links Excellgen http://Excellgen.com
5R01HD034883-12 (2009): $369750
2R01HD034883-11A1 (2008): $369750
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 5T32HD007065-29 from National Institute Of Child Health And Human Development IRG: CHHD
Abstract: Researchers at The Jackson Laboratory have a long and successful track record in training a cadre of research scientists in the complexity of regulation of gene expression and the role of intercellular signaling in developmental decisions in mice. This philosophy, an integral part of the Laboratory s strategic plan, has dictated the ongoing expansion of the overall training program at The Jackson Laboratory, which requests funding for continuation of its well-established postdoctoral research training program in developmental genetics. Fourteen members of The Jackson Laboratory Research Staff form an interdisciplinary pool of trainee preceptors who are investigating pre-implantation and post-implantation embryonic development, germ cell differentiation, eye development, primary sex determination, and the developmental regulation of homeostatic mechanisms in adult animals. These types of analyses are made possible by the availability of the Laboratory s unparalleled resource base of special inbred, spontaneous and induced-mutant mice, and curated knowledge about them. Support is requested for four trainees, who will devote their major effort to bench research, and are integrated into The Laboratory s seminars, courses, workshops, and research interest groups. They are required to write fellowship applications, and present their results both at in-house interest groups and international meetings. Their progress is overseen by a formal Training Committee, in which each member acts as an informal mentor, or liaison, for several trainees. Upon completion of training, participants will be qualified to engage in creative, independent research in developmental genetics at a university, research institution, or in industry. The continued quality of the program is evidenced in part by the fact that eight of the twelve trainees supported by this program in the last reporting period obtained independent fellowships. The primary training facility IS TJL, a private, independent research center. TJL is an NCI-designated Cancer Center, with a research budget of $53.9 million, raises 3 million mice annually, and has held NIH research training grants continuously since 1956.
Project start date: 1977-07-01
Project end date: 2009-04-30
5T32HD007065-29 (2007): $59867
5T32HD007065-28 (2006): $118558
5T32HD007065-27 (2005): $191142
5T32HD007065-30 (2008): $0
Modifiers Of A Mouse Model Of Alagille Syndrome
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 5R01DK066387-04 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG1
Abstract: Alagille syndrome is an autosomal dominant disorder characterized by developmental abnormalities of the liver, heart, eye, skeleton and kidney. Alagille syndrome is due to haploinsufficiency for the Jaggedl (Jag1) gene, which encodes a ligand for the Notch family of transmembrane receptors. We have developed a mouse model of Alagille syndrome. While mice heterozygous for a targeted Jag1 null allele do not exhibit most phenotypes characteristic of humans with Alagille syndrome, mice doubly heterozygous for Jag1 and Notch2 targeted mutations exhibit multiple defects similar to human Alagille syndrome patients. These defects include bile duct paucity, glomerular defects in the kidneys, and atrial and ventricular septal defects in the heart. We have identified additional double heterozygous genetic interactions between the Jagl mutation and mutations in the Dill and Notchl genes. These interactions demonstrate that Jagl mutant mice could be used in sensitized mutagenesis screens. We also found that naturally occurring genetic modifiers exist in the C3H strain that enhance ear vestibular defects and suppress eye defects that occur in Jag1 heterozygous mice. We propose three specific aims to identify and characterize genetic modifiers in this system. The aims of this proposal are to 1) map the C3H genetic modifiers of Jag1 heterozygous phenotypes in the eye and inner ear, and determine if these modifiers affect the liver or kidney phenotypes of the Jagl/Notch2 Alagille syndrome model; 2) perform a sensitized genetic screen for chemically-induced dominant enhancers of the phenotypes of Jag1 heterozygous mice; 3) perform a sensitized genetic screen for chemically-induced recessive suppressors of the embryonic lethality of Jag1 homozygous mutant mice. These studies will enable us to create more representative mouse models of Alagille syndrome, and should provide insight into the variable phenotypic expression observed in Alagille syndrome patients.
Keywords: autosomal dominant trait, developmental disease /disorder, disease /disorder model, gene mutation, genetic marker, laboratory mouse, model design /development, syndrome, bone disorder, eye disorder, gene interaction, heart disorder, kidney disorder, labyrinth, liver disorder, vestibular pathway, genetic mapping, genetic screening, genetically modified animal, molecular cloning, phenotype, polymerase chain reaction
Project start date: 2003-12-15
Project end date: 2008-11-30
5R01DK066387-04 (2007): $518637
5R01DK066387-03 (2006): $518571
5R01DK066387-02 (2005): $515584
1R01DK066387-01 (2004): $496123
Sponsored Links Excellgen http://Excellgen.com
GENETIC ANALYSIS OF THE NOTCH SIGNALING PATHWAY
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 5R01NS036437-03 from National Institute Of Neurological Disorders And Stroke IRG: HED
Abstract: adapted from the investigator s ) The goal of this proposal is to understand the multiple roles that the Notch signaling pathway plays during embryogenesis in mammals. The components of this pathway are highly conserved in evolution, suggesting that this pathway is fundamentally important for cell-cell interactions and the control of differentiation in multicellular organisms. Null mutations of three Notch family genes in mice (Notch1, Notch2, and int-3) have been constructed. Two of these genes (Notch1 and Notch2) are essential for normal embryonic development, confirming the importance of the Notch signaling pathway in mammals. In this proposal, a genetic approach will be used for the functional analysis of the Notch signaling pathway. The prediction that Notch family genes in mice share substantial functional redundancy will be tested by creating three different double mutant combinations, and assessing these double mutants for dosage-sensitive genetic interactions and synergistic effects of the mutations. This proposal will also test the hypothesis that the genes encoding ligands for the Notch family of receptors, like the genes encoding the receptors themselves, are essential for normal embryonic development. This hypothesis will be tested by creating a null mutation of the Jagged gene (a mouse homolog of the Notch ligand Serrate), analyzing the phenotype of homozygous Jagged null mutant embryos and mice, and analyzing interactions between the Jagged mutations and Notch mutations. These studies may further our understanding of the roles of the Notch signaling pathway in mammalian development.
Keywords: biological signal transduction, developmental genetics, embryogenesis, gene expression, mammalian embryology, cell cell interaction, cell differentiation, gene dosage, gene interaction, gene mutation, gestational age, phenotype, receptor expression, embryonic stem cell, gene targeting, genotype, histology, immunocytochemistry, in situ hybridization, laboratory mouse, polymerase chain reaction, radionuclide, tissue /cell culture, transgenic animal
Project start date: 1996-09-09
Project end date: 1999-06-30
5R01NS036437-03 (1998): $260947
5R01NS036437-02 (1997): $250908
Genetic Analysis Of Snail Superfamily Genes In Mice
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory
600 Main St
bar Harbor, Me 046091500
Grant 5R01HD034883-10 from National Institute Of Child Health And Human Development IRG: CDF
Keywords: gene, genetics Aves, Chordata, DNA, DNA binding protein, Gastropoda, RNA, allele, binding protein, binding site, cell, cell differentiation, cell line, embryo implantation, embryogenesis, evolution, family, fish, gel mobility shift assay, gene mutation, human, in situ hybridization, mesoderm, molecular genetics, mutant, nervous system, phenotype, play, protein, protein binding, protein structure, role, stem cell, tissue, tissue /cell culture, trophoblast
Project start date: 1998-01-01
Project end date: 2008-12-31
5R01HD034883-10 (2007): $347746
5R01HD034883-09 (2006): $358132
5R01HD034883-08 (2005): $366750
5R01HD034883-07 (2004): $366750
GENETIC ANALYSIS OF THE NOTCH SIGNALING PATHWAY
Thomas H Gridley, Senior Staff Scientist
Jackson Laboratory 600 Main St Bar Harbor, Me 046091500
Grant 1R01NS036437-01 from National Institute Of Neurological Disorders And Stroke IRG: HED
Project start date: 1996-09-09
Project end date: 1999-06-30
1R01NS036437-01 (1996): $241257