Walter Fontana
Harvard University (medical School)
Project start date: 2010-02-01
Project end date: 2015-01-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Walter Fontana
AUTOMATED ACQUISITION OF C. ELEGANS SURVIVAL CURVES WITH A FLATBED SCANNER
Walter Fontana, Professor
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Grant 5R03AG032481-02 from National Institute On Aging
Abstract: Reactive chemicals and molecular processes occurring in living systems lead to the accumulation of informational and physical damage despite repair mechanisms. This wear-and-tear results in a growing likelihood of disease and death with time, referred to as aging. The random nature of damaging events contributes to the phenotypic divergence of individuals, even when they are genetically identical and share the same environment. This divergence results in a distribution of life spans that is reflective of the genotype. The complete survival curve of a population of isogenic individuals is therefore a powerful tool for classifying genes with regard to their impact on aging. The proposal aims at developing an automated, inexpensive, and robust system for obtaining high-resolution survival curves of the nematode C. elegans. The proposal will achieve this objective by adapting commercial flatbed scanners for long-term imaging of large worm populations and developing appropriate image processing software. Validation of the new method will occur by comparison with traditional manual procedures on four widely studied lifespan- extension mutants. The method´s suitability for RNA interference studies will be assessed using similar comparisons. Such an automated system will have broad impact on the study of aging by revealing subtle genetic and environmental effects on survival that advance our understanding of major aging processes. The survival curve of genetically identical individuals is a powerful tool in the study of aging. An automated, inexpensive, and robust system for obtaining high-resolution survival curves of large worm (C. elegans) populations will have broad impact on the study of aging by revealing subtle genetic and environmental effects on survival that advance our understanding of major aging pathways conserved across species
Keywords: Age; Aging; Aging Process; Aging-Related Process; Animals; C elegans; C.elegans; Caenorhabditis elegans; Cessation of life; Chemicals; Computer Programs; Computer software; Computer-Assisted Image Analysis; Death; Disease; Disorder; Environment; Event; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genotype; Hour; Image; Image Analyses; Image Analyses, Computer-Assisted; Image Analysis; Individual; Lead; Length of Life; Longevity; Manuals; Methods; Modification; Molecular; Motion; Movement; Mutation; Nature; Nematoda; Nematodes; Organism; Pathway interactions; Pb element; Platinum; Platinum Black; Population; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Posture; Procedures; Process; Proxy; Pt element; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; ROC Analysis; Resolution; Senescence; Sequence-Specific Posttranscriptional Gene Silencing; Software; Speed; Speed (motion); System; System, LOINC Axis 4; Time; Validation; body movement; computer program/software; content based retrieval; disease/disorder; feature detection; feature recognition; genome mutation; heavy metal Pb; heavy metal lead; image evaluation; image processing; imaging; knock-down; life span; lifespan; living system; mutant; pathway; public health relevance; repair; repaired; response; roundworm; senescent; tool
Project start date: 2008-09-01
Project end date: 2010-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: PA-06-180
5R03AG032481-02 (2009): $69495
1R03AG032481-01 (2008): $69290
3R03AG032481-02S1 (2009): $132635
THE VARIABILITY OF THE LIFESPAN PHENOTYPE IN C.ELEGANS
Walter Fontana, Professor
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Grant 1R01AG034994-01 from National Institute On Aging
Abstract: Aging is a process shaped by genetics, environment, and chance, all of which conspire to determine an individuals´ time of death. A survival curve constitutes the demographic signature of aging at the level of the population. Understanding the survival curve´s responsiveness to genetic interventions is a critical step in guiding the development of more structured models of aging. Such models may give insight into the processes that determine the patterns of initiation and progression of age-related diseases, such Alzheimer´s and Parkinson´s disease and many types of cancer. Large amounts of demographic information are required to support such modeling efforts, and data-acquisition remains a limiting step in contemporary research. We have recently developed a method that greatly accelerates the collection of demographic aging data in C. elegans nematodes, via the automated acquisition of survival curves at high statistical and temporal resolution. This method utilizes modified consumer-electronics flatbed scanners to image worms cultured under standard conditions. Accompanying software automatically processes the resultant time-lapse videos into survival curves. We will use this technology to link genetic and environmental perturbations to a high-precision demographic aging signature at an unprecedented scale. We will acquire and analyze high-resolution lifespan distributions for roughly 2000 mutants representing all classic genes known to affect lifespan in this organism as well as a variety of targeted gene families. We will determine whether survival curves deviate from predictions made by classic aging models and apply functional data analysis to gain insight into the number and nature of dimensions along which the demographic aging signature is most variable. We will group genes into categories in terms of their impact on survival curve shape features, in order to place known gene functions in relation to the demographic aging signature and help illuminate unknown gene functions. This information will be important for future mechanistic studies, and will offer perspective for existing molecular knowledge. We will make our collection of survival curves widely available, thus providing a valuable resource to both the C. elegans research community and demographers. Animals ranging from worms to humans become frail, disease prone, and more likely to die as they age. We will use an automated method for measuring death times of C. elegans nematodes to probe why some individuals die sooner than others. By observing the effect of 2,000 separate gene mutations on aging worm populations, this project will provide insight about how genes work together to affect the aging process
Keywords: ATP-protein phosphotransferase; Affect; Age; Aging; Aging Process; Aging, Demographic; Aging-Related Process; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Analysis, Data; Animals; Assay; Attention; Bioassay; Biologic Assays; Biological Assay; C elegans; C.elegans; Caenorhabditis elegans; Categories; Cessation of life; Code; Coding System; Collection; Communities; Computer Programs; Computer software; Cues; Culture Procedure; DNA Alteration; DNA mutation; Data; Data Analyses; Death; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Demographer; Demographic Aging; Descriptor; Development; Dimensions; Disease; Disorder; Electronics; Environment; Future; Gene Alteration; Gene Family; Gene Mutation; Gene Transfer Clinical; Gene Transfer Procedure; Gene variant; Gene-Tx; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic Diversity; Genetic Intervention; Genetic Variation; Genetic defect; Genetic mutation; Genome; Genotype; Human; Human, General; INSR; Idiopathic Parkinson Disease; Image; Image Analyses; Image Analysis; Imagery; Individual; Insulin Receptor; Insulin Receptor Protein-Tyrosine Kinase; Insulin-Dependent Tyrosine Protein Kinase; Intervention, Genetic; Knowledge; Laboratory culture; Length of Life; Lewy Body Parkinson Disease; Link; Longevity; Man (Taxonomy); Man, Modern; Manuals; Maps; Measures; Methods; Modeling; Molecular; Molecular Biology, Gene Therapy; Mortality; Mortality Vital Statistics; Movement; Mutation; Nature; Nematoda; Nematodes; Organism; Paralysis Agitans; Parental Ages; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathway interactions; Pattern; Phenotype; Population; Population Characteristics; Primary Parkinsonism; Primary Senile Degenerative Dementia; Procedures; Process; Protein Kinase; Protocol; Protocols documentation; ROC Analysis; Reporting; Research; Research Resources; Resolution; Resources; Risk; Running; SCHED; Sampling; Schedule; Senescence; Sequence Alteration; Series; Shapes; Side; Software; Structure; Survey Instrument; Surveys; Technology; Temperature; Testing; Therapy, DNA; Time; Variant; Variation; Variation (Genetics); Visualization; Work; age dependent; age effect; age related; aging effect; allelic variant; base; body movement; cancer type; computer program/software; data acquisition; dementia of the Alzheimer type; disease/disorder; dosage; gene function; gene therapy; genetic therapy; genome mutation; glycogen synthase a kinase; hazard; hydroxyalkyl protein kinase; image evaluation; imaging; insight; life span; lifespan; living system; mutant; pathway; phosphorylase b kinase kinase; primary degenerative dementia; public health relevance; reproductive; roundworm; senescent; senile dementia of the Alzheimer type; transcription factor
Relevance: Animals ranging from worms to humans become frail, disease prone, and more likely to die as they age. We will use an automated method for measuring death times of C. elegans nematodes to probe why some individuals die sooner than others. By observing the effect of 2,000 separate gene mutations on aging worm populations, this project will provide insight about how genes work together to affect the aging process
Project start date: 2010-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
1R01AG034994-01 (2010): $316088