DEVELOPMENT OF XENOPUS AS A MODEL TO STUDY CONGENITAL HEART DISEASE
Ann F Ramsdell
University Of South Carolina At Columbia, 901 Sumter Street, Columbia, Sc 29208
Grant 5K02HL086737-04 from National Heart, Lung, And Blood Institute
Abstract: The objective of this proposal is to substantially increase protected research time in order to boost productivity on a currently funded R01 (and its pending renewal) while positioning the candidate to successfully compete for a second major grant (i.e. a new R01 or a project on a programmatic grant). The candidate holds a joint faculty position between two state universities located ~120 miles apart. Travel, teaching and service obligations leave 45% time available for research. Support by a K02 award would release the candidate from most teaching and service assignments, generating 80-95% time over the next five years to be spent exclusively on research. The overall objectives of the candidate´s funded R01 and pending renewal are to discover fundamental mechanisms of heart development, and to determine how they are affected by laterality genes during cardiac (dys)morphogenesis. To achieve this, the candidate has established an experimentally-induced heterotaxy model in embryos of the frog, Xenopus laevis. The heterotaxy embryos exhibit abnormal cardiac and visceral organ L-R asymmetries that are accompanied by complex, congenital heart defects (CHDs). Using an innovative cell labeling strategy to produce the first L-R cell lineage map of the vertebrate heart, the candidate discovered that L-R cell lineage composition is anomalous in heterotaxy hearts, and that the L-R lineage defects co-localize with structural CHDs. Based on these results and others, the K02 Aims are to identify in Xenopus the cardiac cell populations that, together with working cardiomyocytes derived from the primary heart fields, build the heart secondary heart field, cardiac neural crest, and cardiac conduction system. These Aims will be accomplished by spending "minisabbaticals" in leading labs to adapt functional (laser-assisted tissue ablation, echocardiography, optical activation mapping) and additional embryological techniques (caged fluorescent dextrans, tissue grafting) for use in Xenopus. This will be complemented by coursework and participation in professional meetings. Data from the K02 Aims will be used to propose and test novel hypotheses on the role that L-R lineage composition in various cardiac cell populations play in cardiac (dys)morphogenesis. The significance of this work will be to elucidate conserved mechanisms of heart development, which in turn, will identify genes and inductive processes that may cause CHDs if affected by genetic or environmental perturbations. (End of )
Keywords: Ablation; Address; Affect; Anterior; Antibodies; Articulation; Atrial; Auricle of Heart; Body Tissues; Cardiac; Cardiac Abnormalities; Cardiac Atrium; Cardiac Defects, Congenital; Cardiac Malformation; Cardiac Myocytes; Cardiac Output; Cardiac conduction system; Cardiac defect; Cardiocyte; Cell Lineage; Cells; Chronotropism, Cardiac; Chronotropisms, Cardiac; Coloring Agents; Complement; Complement Proteins; Complex; Computer Systems Development; Congenital Heart Defects; Congenital malformation of cardiac septum; Data; Defect; Development; Development, Computer Systems; Developmental Process; Dextrans; Dyes; Dysfunction; EFRAC; Echocardiogram; Echocardiography; Educational process of instructing; Ejection Fraction; Electromagnetic, Laser; Embryo; Embryo Development; Embryogenesis; Embryonic; Embryonic Development; Exhibits; FLR; Faculty; Failure (biologic function); Foundations; Frog; Functional disorder; Funding; Future; Genes; Genetic; Grant; Handedness; Heart; Heart Abnormalities; Heart Atrium; Heart Conduction System; Heart Defects, Congenital; Heart Malformation; Heart Rate; Heart Septal Defects; Heart myocyte; Histologic; Histologically; ISA; Independent Scientist Award; Individual; Investigation; Investigators; Isomerism; Joints; K02 Award; Label; Lasers; Laterality; Left; Life; Maps; Mesoderm; Method LOINC Axis 6; Methodology; Methods and Techniques; Methods, Other; Modeling; Molecular; Morphogenesis; Muscle Cells, Cardiac; Muscle Cells, Heart; Myocytes, Cardiac; N element; N2 element; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neural Crest; Nitrogen; Optics; Organ; Pathway interactions; Pattern; Physiologic pulse; Physiology; Physiopathology; Platanna; Play; Population; Position; Positioning Attribute; Process; Productivity; Progress Reports; Pulse; Radiation, Laser; Rana; Rana (genus); Research; Research Personnel; Researchers; Role; Services; Signal Pathway; Situs Inversus; Solid; Source; Stroke Volume; Syndrome; System; System, LOINC Axis 4; Systems Development; Teaching; Techniques; Testing; Time; Tissue Grafts; Tissues; Transthoracic Echocardiography; Travel; United States National Institutes of Health; Universities; Ventricular; Vertebrate Animals; Vertebrates; Visceral; Work; Xenopus; Xenopus laevis; atrium; base; cardiac rhythm; cardiac septal defect; cardiac septal deformity; cardiac septum defect; cardiac septum deformity; cardiogenesis; cardiomyocyte; congenital cardiac disorder; congenital cardiac septum defect; congenital heart disease; congenital heart disorder; congenital heart septum defect; congenital malformation of septum; dextran; failure; heart defect; heart development; heart output; heart rhythm; heart septal deformity; heart septum defects; heart septum deformity; heart sonography; heterotaxia syndrome; heterotaxy; innovate; innovation; innovative; inversion of viscera; isomer; laterality sequence; malformation; meetings; molecular marker; novel; pathophysiology; pathway; septal defect; septum defect; situs abnormality; situs inversus viscerum; social role; sound measurement; tissue grafting; tool; transposition of viscera; vertebrata; visceral heterotaxy; visceral transposition; xenopus development
Project start date: 2007-09-01
Project end date: 2012-05-31
Budget start date: 1-AUG-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-06-527
5K02HL086737-04 (2010): $103929
Sponsored Links Excellgen http://Excellgen.com
DEVELOPMENT OF XENOPUS AS A MODEL TO STUDY CONGENITAL HEART DISEASE
Ann F Ramsdell, Associate Professor
University Of South Carolina At Columbia, 901 Sumter Street, Columbia, Sc 29208
Grant 5K02HL086737-03 from National Heart, Lung, And Blood Institute
Abstract: The objective of this proposal is to substantially increase protected research time in order to boost productivity on a currently funded R01 (and its pending renewal) while positioning the candidate to successfully compete for a second major grant (i.e. a new R01 or a project on a programmatic grant). The candidate holds a joint faculty position between two state universities located ~120 miles apart. Travel, teaching and service obligations leave 45% time available for research. Support by a K02 award would release the candidate from most teaching and service assignments, generating 80-95% time over the next five years to be spent exclusively on research. The overall objectives of the candidate´s funded R01 and pending renewal are to discover fundamental mechanisms of heart development, and to determine how they are affected by laterality genes during cardiac (dys)morphogenesis. To achieve this, the candidate has established an experimentally-induced heterotaxy model in embryos of the frog, Xenopus laevis. The heterotaxy embryos exhibit abnormal cardiac and visceral organ L-R asymmetries that are accompanied by complex, congenital heart defects (CHDs). Using an innovative cell labeling strategy to produce the first L-R cell lineage map of the vertebrate heart, the candidate discovered that L-R cell lineage composition is anomalous in heterotaxy hearts, and that the L-R lineage defects co-localize with structural CHDs. Based on these results and others, the K02 Aims are to identify in Xenopus the cardiac cell populations that, together with working cardiomyocytes derived from the primary heart fields, build the heart secondary heart field, cardiac neural crest, and cardiac conduction system. These Aims will be accomplished by spending "minisabbaticals" in leading labs to adapt functional (laser-assisted tissue ablation, echocardiography, optical activation mapping) and additional embryological techniques (caged fluorescent dextrans, tissue grafting) for use in Xenopus. This will be complemented by coursework and participation in professional meetings. Data from the K02 Aims will be used to propose and test novel hypotheses on the role that L-R lineage composition in various cardiac cell populations play in cardiac (dys)morphogenesis. The significance of this work will be to elucidate conserved mechanisms of heart development, which in turn, will identify genes and inductive processes that may cause CHDs if affected by genetic or environmental perturbations. (End of )
Keywords: Ablation; Address; Affect; Anterior; Antibodies; Articulation; Atrial; Auricle of Heart; Body Tissues; Cardiac; Cardiac Abnormalities; Cardiac Atrium; Cardiac Defects, Congenital; Cardiac Malformation; Cardiac Myocytes; Cardiac Output; Cardiac conduction system; Cardiac defect; Cardiocyte; Cell Lineage; Cells; Chronotropism, Cardiac; Chronotropisms, Cardiac; Coloring Agents; Complement; Complement Proteins; Complex; Computer Systems Development; Congenital Heart Defects; Congenital malformation of cardiac septum; Data; Defect; Development; Development, Computer Systems; Developmental Process; Dextrans; Dyes; Dysfunction; EFRAC; Echocardiogram; Echocardiography; Educational process of instructing; Ejection Fraction; Electromagnetic, Laser; Embryo; Embryo Development; Embryogenesis; Embryonic; Embryonic Development; Exhibits; FLR; Faculty; Failure (biologic function); Foundations; Frog; Functional disorder; Funding; Future; Genes; Genetic; Grant; Handedness; Heart; Heart Abnormalities; Heart Atrium; Heart Conduction System; Heart Defects, Congenital; Heart Malformation; Heart Rate; Heart Septal Defects; Heart myocyte; Histologic; Histologically; ISA; Independent Scientist Award; Individual; Investigation; Investigators; Isomerism; Joints; K02 Award; Label; Lasers; Laterality; Left; Life; Maps; Mesoderm; Method LOINC Axis 6; Methodology; Methods and Techniques; Methods, Other; Modeling; Molecular; Morphogenesis; Muscle Cells, Cardiac; Muscle Cells, Heart; Myocytes, Cardiac; N element; N2 element; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neural Crest; Nitrogen; Optics; Organ; Pathway interactions; Pattern; Physiologic pulse; Physiology; Physiopathology; Platanna; Play; Population; Position; Positioning Attribute; Process; Productivity; Progress Reports; Pulse; Radiation, Laser; Rana; Rana (genus); Reports, Progress; Research; Research Personnel; Researchers; Role; Services; Signal Pathway; Situs Inversus; Solid; Source; Stroke Volume; Syndrome; System; System, LOINC Axis 4; Systems Development; Teaching; Techniques; Testing; Time; Tissue Grafts; Tissues; Transthoracic Echocardiography; Travel; United States National Institutes of Health; Universities; Ventricular; Vertebrate Animals; Vertebrates; Visceral; Work; Xenopus; Xenopus laevis; ing; atrium; base; cardiac rhythm; cardiac septal defect; cardiac septal deformity; cardiac septum defect; cardiac septum deformity; cardiogenesis; cardiomyocyte; congenital cardiac disorder; congenital cardiac septum defect; congenital heart disease; congenital heart disorder; congenital heart septum defect; congenital malformation of septum; dextran; failure; heart defect; heart development; heart output; heart rhythm; heart septal deformity; heart septum defects; heart septum deformity; heart sonography; heterotaxia syndrome; heterotaxy; innovate; innovation; innovative; inversion of viscera; isomer; laterality sequence; malformation; meetings; molecular marker; novel; pathophysiology; pathway; septal defect; septum defect; situs abnormality; situs inversus viscerum; social role; sound measurement; tissue grafting; tool; transposition of viscera; vertebrata; visceral heterotaxy; visceral transposition; xenopus development
Project start date: 2007-09-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
PFA/PA: PA-06-527
5K02HL086737-03 (2009): $103929
5K02HL086737-02 (2008): $103929
Grants awarded to Ann F Ramsdell
Development Of Xenopus As A Model To Study Congenital Heart Disease
Ann F Ramsdell
Cell And Developmental Biology And Anatomyuniversity Of South Carolina At Columbia
901 Sumter Street
columbia, Sc 29208
Grant 1K02HL086737-01A1 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The objective of this proposal is to substantially increase protected research time in order to boost productivity on a currently funded R01 (and its pending renewal) while positioning the candidate to successfully compete for a second major grant (i.e. a new R01 or a project on a programmatic grant). The candidate holds a joint faculty position between two state universities located ~120 miles apart. Travel, teaching and service obligations leave 45% time available for research. Support by a K02 award would release the candidate from most teaching and service assignments, generating 80-95% time over the next five years to be spent exclusively on research. The overall objectives of the candidate´s funded R01 and pending renewal are to discover fundamental mechanisms of heart development, and to determine how they are affected by laterality genes during cardiac (dys)morphogenesis. To achieve this, the candidate has established an experimentally-induced heterotaxy model in embryos of the frog, Xenopus laevis. The heterotaxy embryos exhibit abnormal cardiac and visceral organ L-R asymmetries that are accompanied by complex, congenital heart defects (CHDs). Using an innovative cell labeling strategy to produce the first L-R cell lineage map of the vertebrate heart, the candidate discovered that L-R cell lineage composition is anomalous in heterotaxy hearts, and that the L-R lineage defects co-localize with structural CHDs. Based on these results and others, the K02 Aims are to identify in Xenopus the cardiac cell populations that, together with working cardiomyocytes derived from the primary heart fields, build the heart secondary heart field, cardiac neural crest, and cardiac conduction system. These Aims will be accomplished by spending "minisabbaticals" in leading labs to adapt functional (laser-assisted tissue ablation, echocardiography, optical activation mapping) and additional embryological techniques (caged fluorescent dextrans, tissue grafting) for use in Xenopus. This will be complemented by coursework and participation in professional meetings. Data from the K02 Aims will be used to propose and test novel hypotheses on the role that L-R lineage composition in various cardiac cell populations play in cardiac (dys)morphogenesis. The significance of this work will be to elucidate conserved mechanisms of heart development, which in turn, will identify genes and inductive processes that may cause CHDs if affected by genetic or environmental perturbations. (End of )
Keywords: Xenopus, biological model, cardiogenesis, congenital heart disorder, developmental genetics, nonmammalian vertebrate embryology antisense nucleic acid, cell population study, heart conduction system, heart contraction, heart rhythm, morphology, neural crest echocardiography, electrophysiology, laser
Project start date: 2007-09-01
Project end date: 2012-07-31
1K02HL086737-01A1 (2007): $103929
Left-Right Axis Determination And Cardiac Development
Ann F Ramsdell
University Of South Carolina At Columbia 901 Sumter Street Columbia, Sc 29208
Grant 5R01HL073270-04 from National Heart, Lung, And Blood Institute IRG: CDF
Abstract: The majority of complex congenital heart defects occur in individuals who are also afflicted by laterality disease, reflecting the extreme susceptibility of the developing heart to disturbances in left-right (LR) patterning processes. The objective of this proposal is to identify inductive mechanisms that generate the LR body plan and to elucidate how cardiac cells use this positional "blueprint" to develop LR asymmetries. With focus on receptors for the transforming growth factor-Beta superfamily, we have found that two Activin-Like Kinases--ALK2 and ALK4--are both necessary and sufficient for LR development of the heart (and other organs) in embryos of the frog, Xenopus Iaevis. Taking advantage of the range of experimental manipulations that is uniquely possible in Xenopus, we will test the hypothesis that ALK2 and ALK4 modulate cardiac LR development by playing pivotal roles in LR axis determination. Using both biochemical and loss-of-function analyses, Aim 1 will identify cell-cell signals important for LR axis formation by defining ligands for the ALK pathways. Using classic transplantation and co-culture assays, Aim 2 will position ALK pathways in the context of cell-cell interactions already known to be important for LR patterning by determining whether ALKs relay positional signals to the midline. Because many of the molecules involved in midline specification and other LR relay interactions are not known, Aim 3 will fill in some of these gaps by identifying genes that function upstream, downstream, or within ALK pathways. This will be accomplished by performing a high throughput expression cloning screen in which new laterality genes already have been, and will continue to be, identified by . Using in vivo lineage labeling, Aim 4 will address how cardiac cells utilize LR patterning information by determining whether ALK signaling culminates in specific asymmetric cell contributions from the paired left and right heart fields to different segments of the "straight" heart tube. Together, our results will contribute new knowledge that is necessary to accelerate progress in the intersecting fields of embryonic heart formation and vertebrate LR development. The long-term significance of the work will be to identify genes and inductive processes that may result in congenital cardiac (and other) LR defects if affected by genetic or environmental perturbations.
Keywords: congenital cardiovascular disorder, growth /development, heart cell, histogenesis, morphology, orientation, biological signal transduction, cell cell interaction, gene expression, gene induction /repression, growth factor receptor, inhibin, nonmammalian vertebrate embryology, protein tyrosine kinase, transforming growth factor, Xenopus, Xenopus oocyte, biomarker, gene targeting, high throughput technology, molecular cloning, transplantation
Project start date: 2002-09-01
Project end date: 2008-07-31
5R01HL073270-04 (2005): $291000
5R01HL073270-03 (2004): $291000