Jocelyn A Mcdonald
Cleveland Clinic Lerner Col/med-cwru
Project start date: 2008-03-10
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
REGULATION OF IN VIVO CELL MIGRATION BY THE POLARITY PROTEIN PAR-1
Jocelyn A Mcdonald
Cleveland Clinic Lerner Col/med-cwru, Jjn5-01, Cleveland, Oh 44195
Grant 5R01GM078526-03 from National Institute Of General Medical Sciences
Keywords: No Project Terms available
Project start date: 2008-03-10
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01GM078526-03 (2010): $295317
Grants awarded to Jocelyn A Mcdonald
A GENETIC ANALYSIS OF CELL MIGRATION IN DROSOPHILA
Jocelyn A Mcdonald
Biological Chemistryjohns Hopkins University
w400 Wyman Park Building
baltimore, Md 212182680
Grant 5F32GM020539-02 from National Institute Of General Medical Sciences IRG: BIOL
Abstract: Regulated cell migration is an important component of many biological processes, including wound repair and development, and one that goes away in cancer, resulting in tumor invasion and metastasis. The border cells, a small group of migratory cells in the Drosophila ovary, are an ideal system for dissecting the molecular mechanisms of cell migration. Although several genes convert border cells from a stationary to migratory state, only a few genes are known to initiate migration after this step. The goal of this proposal is to identify new genes directly involved in promoting border cell migration. Two lethal mutations, 17E1 and 27C1, were identified in a screen for mutations that cause border cell migration defects in mosaic clones. These two mutations dominantly interact, such that females heterozygous for both mutations exhibit defective border cell migration. Since the expression of several border cell markers is normal in each of the mutants, the genes disrupted by 17E1 and 27C1 may directly control border cell migration rather than specify border cell identity. I will conduct a detailed analysis of the roles of 17E1 and 27C1 in cell migration by examining their effect on the distribution of border cell markers and on the migration of other cell types. The genes will be mapped and cloned using standard molecular and genetic approaches. Finally, a genetic screen will be conducted to identify deficiencies that dominantly interact with 27C1 to disrupt border cell migration
Keywords: cell migration, gene expression, genetic regulation, oogenesis cytogenetics, gene mutation Drosophilidae, genetic mapping, molecular cloning
5F32GM020539-02 (2001): $40196
1F32GM020539-01 (2000): $32416
REGULATION OF IN VIVO CELL MIGRATION BY THE POLARITY PROTEIN PAR-1
Jocelyn A Mcdonald
Cleveland Clinic Lerner Col/med-cwru, Jjn5-01, Cleveland, Oh 44195
Grant 3R01GM078526-02S1 from National Institute Of General Medical Sciences
Abstract: Cell migration is essential for many aspects of normal embryonic development as well as in wound healing in the adult. Failure of cells to migrate contributes to birth defects and difficulties in wound healing, whereas unregulated cell migration triggers tumor metastasis in cancer. Therefore, it is of fundamental importance to understand how cells migrate, both in normal processes and in diseases such as cancer. The long-term goal of our research is to identify critical molecules that control guided cell migration within a living organism. To this end, we study the simple migration of the border cells, a group of follicle cells in the Drosophila ovary. These cells develop from a continuous, polarized epithelium from which they break away and invade the surrounding germline. Thus, border cells are an excellent model for identifying the genetic and molecular mechanisms that control tumor invasion and metastasis. Although some of the proteins that regulate border cell migration have been identified, questions remain. For example, little is known about what regulates detachment of border cells from the epithelium. In addition, only a few molecular pathways are known to promote the polarized, dynamic protrusions that direct cell migration. To better understand how these and other aspects of border cell migration are regulated, we identified a mutation in par-1 that disrupted border cell migration in mosaic mutant clones. Par-1 is a highly conserved serine-threonine kinase that functions in cell polarity, microtubule stability, and Wnt signaling, but has not been previously implicated in regulating cell migration. In preliminary studies, we found that Par-1 functions in border cells and adjacent follicle cells and that half the border cells mutant for par-1 completely fail to migrate. Thus, Par-1 likely regulates an early step in the migration process. A known downstream target of Par-1, the Wnt signaling pathway component Disheveled (Dsh), regulates cellular protrusions in vertebrates, and we found that Dsh regulates normal border cell migration. Unexpectedly, we identified an allele of patched in a dominant genetic modifier screen of par-1-dependent border cell migration. Patched is the receptor for the Hedgehog (Hh) glycoprotein, suggesting that Hh signaling functions in Par-1-mediated border cell migration. The goal of this proposal is to further investigate the precise functions of Par-1 and its partners. We will use a powerful new live imaging technique, along with genetic, molecular and immunofluorescence techniques to address the following Specific Aims (1) Determine the role of Par-1 in regulation of normal border cell migration; (2) Investigate the role of the Par-1 target Dsh in border cells; (3) Characterize the role of Patched in Par-1 signaling and border cell migration. These studies are anticipated to provide new insights into the mechanisms of cell migration in a living organism, which will lead to a better understanding and treatment of diseases such as cancer. Cells move (migrate) in a variety of normal processes, whereas abnormally migrating cells contribute to birth defects, cannot close wounds, and trigger tumor metastasis. Using a simple model system, we found that a protein called Par-1 regulates cell invasion and migration. The goal of this study is to better understand the mechanisms that Par-1 and its protein partners use to regulate normal cell migration, with the hope that they will provide new therapeutic targets in human tumor metastasis and wound healing
Keywords: 21+ years old; Address; Adult; Affect; Alleles; Allelomorphs; Anterior; Antimorphic mutation; Biological Models; Birth Defects; Body Tissues; CAM 120/80; Cadherin-1; Cancers; Cell Communication and Signaling; Cell Locomotion; Cell Migration; Cell Movement; Cell Polarity; Cell Signaling; Cell-Cell Adhesion; Cells; Cellular Migration; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Malformation; Coon`s Technic; Coon`s Technique; Development; Disease; Disorder; Dominant Genetic Conditions; Dominant Negative; Dominant trait; Dominant-Negative Mutant; Dominant-Negative Mutation; Drosophila; Drosophila genus; E-Cadherin; Embryo Development; Embryogenesis; Embryonic Development; Epithelial Calcium-Dependent Adhesion Protein; Epithelial Cells; Epithelial-Cadherin; Epithelium; Erinaceidae; Exhibits; FLR; Failure (biologic function); Fluorescent Antibody Technic; Fluorescent Antibody Technique; Fluorescent Antinuclear Antibody Test; Fruit Fly, Drosophila; Gene-Modified; Genes; Genetic Alteration; Genetic Change; Genetic Dominant; Genetic Screening; Genetic defect; Genital System, Female, Ovary; Glycoproteins; Goals; Hedgehogs; Human; Human, Adult; Human, General; Imaging Procedures; Imaging Techniques; Immigrations; Immunofluorescence Technic; Immunofluorescence Technique; In Vitro; In-Migration; Intracellular Communication and Signaling; Invaded; Lead; Life; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Mechanics; Mediating; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Micro-tubule; Microtubules; Model System; Modeling; Models, Biologic; Molecular; Molecular Genetic; Molecular Genetic Abnormality; Molecular Genetics; Motility; Motility, Cellular; Mutation; Neoplasm Metastasis; Normal Cell; Normal Tissue; Normal tissue morphology; Organism; Ovary; Pathway interactions; Pb element; Phenotype; Play; Process; Protein-Serine Kinase; Protein-Serine-Threonine Kinases; Protein-Threonine Kinase; Proteins; Receptor Protein; Regulation; Research; Role; Scaffolding Protein; Secondary Neoplasm; Secondary Tumor; Serine Kinase; Serine-Threonine Kinases; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Technics, Imaging; Testing; Threonine Kinase; Tissues; Transgenes; Tumor Cell Invasion; Tumor Cell Migration; Tumor Invasion; Uvomorulin; Vertebrate Animals; Vertebrates; Wound Healing; Wound Repair; adult human (21+); biological signal transduction; cancer metastasis; cell motility; cellular polarity; disease/disorder; egg; failure; fluorescent antibody; fruit fly; gene product; genetic manipulation; genome mutation; heavy metal Pb; heavy metal lead; in vivo; insight; living system; loss of function; malignancy; migration; mutant; neoplasm/cancer; new therapeutic target; pathway; polarized cell; protein function; receptor; social role; tissue repair; tumor; vertebrata
Project start date: 2009-09-29
Project end date: 2011-08-31
Budget start date: 29-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
3R01GM078526-02S1 (2009): $143203