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Cammarato Lab Projects
1R01HL124091 (Cammarato, P.I.)
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
Here, we propose to use a transgenic animal model system, Drosophila melanogaster (the fruit fly), to define the mechanisms by which mutations in various thin filament components lead to human cardiac disease. We will produce several new models of actin and troponin-T-based cardiomyopathies to determine the molecular defects that drive diverse and complex tissue remodeling. Finally, in vivo genetic suppression experiments, designed to ameliorate cardiac decline during troponin-T-mediated disease, will resolve novel interactions among thin filament components involved in regulating muscle contraction.
R01 GM32443 (Bernstein, P.I.)
Genetics and Molecular Biology of Striated Muscle Myosin
The goal of this project is to examine the mechanism by which the myosin molecular motor functions in striated muscle. Using a transgenic model system, the fruit fly Drosophila melanogaster, we will produce models of human myosin-based muscle disease (distal arthrogryposis) and heart disease (hypertrophic cardiomyopathy) to determine the molecular defects that cause abnormal skeletal and cardiac muscle function. We will use genetic suppression and drug treatment to better understand the bases of myosin malfunction and to develop our model system as a means of testing potential therapeutic approaches.
R01 AG045428 (Engler, P.I.)
Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction
The goal of this project is to examine how specific intercalated disc proteins, which are upregulated with age as a part of a genotype, alter the age-associated performance and mechanical stiffness of the Drosophila heart tube. Data from this rapidly aging, genetically tractable model system will be correlated with aged mammalian systems (with and without dysfunction) to assess the predictive power of the fly model in determining age-associated negative changes in heart performance.
AFAR Research Grant
Cammarato, A., P.I.
American Federation for Aging Research
Determining and manipulating age-dependent changes in myocardial stiffness, in vivo. The specific aims of the project are: 1) Identify differences in potential collective, age-related myocardial stiffening events among multiple Drosophila control lines. We will ascertain passive mechanical differences in young vs. old fly hearts from several control strains including Oregon-R, w1118, Canton-S and GMH5-GAL4 x yw. 2) Investigate the effect of aging on passive mechanical properties of Drosophila myocardium with cardiac-specific overexpression of the transcription factor FOXO, which is known to rejuvenate cardiac performance and promote muscle proteostasis in senescent flies. 3) Employ targeted, cardiac-specific RNA interference to improve morphology, performance and mechanics of senescent hearts.
Scientist Development Grant
Cammarato, A., P.I.
American Heart Association (AHA) National Center, 10SDG4180089
Identifying and manipulating age- and mutation-dependent modifiers of cardiac function using the Drosophila model. The specific aims of the project are: 1) Identify age-related changes in cardiac expression profiles using GeneChip microarrays that represent the complete Drosophila genome. This will be done for young and old wildtype fly hearts and for the hearts of two myosin heavy chain mutants and a troponin mutant. 2) Employ RNA interference to knockdown specific cardiac transcripts to determine their role in myopathic responses to the myosin mutations.