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Role of microRNAs in mammalian development and disease
The fundamental aim of our research is to dissect the contribution of individual microRNAs (miRNAs) to posttranscriptional gene targeting in mammalian development and disease. The laboratory makes use of miRNA knockout mice and transgenic mice. We utilize a multi-threaded approach involving histologic, molecular, biochemical, and surgical interventions of mice. We also make use of genome-wide approaches such as microarrays, AGO2 immunoprecipitation, and next generation sequencing to reveal the key circuitry or "targetomes" of miRNAs. The laboratory is currently interrogating the roles of miR-22, miR-100, and let-7 miRNA gene families with engineered mouse models.
Role of miR-22 in heart failure: Adult cardiac hypertrophy or growth is initially beneficial as a compensatory mechanism to assist the heart to normalize wall stress and permit normal cardiovascular function under conditions of extrinsic or intrinsic pathologic stresses, such as hypertension. However, prolongation of this process presents a risk factor for congestive heart failure, arrhythmias, and sudden death. Using a microRNA-22 (miR-22)-deficient mouse model, we found that miR-22 acts to influence cardiac performance during acute and chronic hemodynamic stress in the heart. Although ablation of miR-22 did not lead to overt cardiac structural and functional defects in unstressed adult hearts it led to reduced sarcoplasmic reticulum (SR) calcium content and SR calcium ATPase (SERCA2) expression and activity. At the molecular level loss of miR-22 also impaired global cardiac mRNA expression. Furthermore, absence of miR-22 sensitized mice to cardiac dilation, fibrosis, and heart failure by pressure overload stimulation. Mechanistically these phenotypes were linked to increased expression of various targets of miR-22, including purine-rich element binding protein B (PURB) a highly conserved transcriptional repressor of muscle gene expression. The laboratory is currently evaluating the mechanism(s) and effectors of miR-22 in the heart in greater detail. Ultimately these studies will allow us to understand those pathways and genes that enhance susceptibility to heart failure.
Selected Publications
Rodriguez A*, Oliver H*, Zou H, Chen P, Wang X, Abrams JM (1999) Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nature Cell Biology 1:272-279. (*equal contribution)
Leulier F, Rodriguez A, Khush RS, Abrams JM, Lemaitre B (2000) The Drosophila
caspase Dredd is required to resist gram-negative bacterial infection. EMBO Reports
1:353-358.
Rodriguez A, Chen P, Oliver H, Abrams JM (2002) Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog, Dark. EMBO Journal 21:2189-2197.
Chew SK, Akdemir F, Chen P, Lu WJ, Mills K, Daish T, Kumar S, Rodriguez A, Abrams JM (2004) The apical caspase dronc governs programmed and unprogrammed cell death in Drosophila. Developmental Cell 7:897-907.
Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A (2004) Identification of mammalian microRNA host genes and transcription units. Genome Research 14:1902-1910. (Journal Cover)
Sang TK, Li C, Liu W, Rodriguez A, Abrams JM, Zipursky SL, Jackson GR (2005)
Inactivation of Drosophila Apaf-1 related killer suppresses formation of
polyglutamine aggregates and blocks polyglutamine pathogenesis. Human Molecular Genetics
14:357-372.
Akdemir F, Farkas R, Chen P, Juhasz G, Medved'ová L, Sass M, Wang L, Wang X,
Chittaranjan S, Gorski SM, Rodriguez A, Abrams JM (2006) Autophagy occurs upstream or
parallel to the apoptosome during histolytic cell death. Development 133:1457-1465.
Rodriguez A*, Vigorito E*, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608-611. (*Equal contribution.)
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, Das PP, Miska EA, Rodriguez A, Bradley A, Smith KG, Rada C, Enright AJ, Toellner KM, Maclennan IC, Turner M (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27:847-859.
Gurha P, Abreu-Goodger C, Wang T, Ramirez MO, Drummond AL, van Dongen S, Chen
Y, Bartonicek N, Enright AJ, Lee B, Kelm RJ Jr, Reddy AK, Taffet GE, Bradley A,
Wehrens XH, Entman ML, Rodriguez A (2012) Targeted deletion of microRNA-22 promotes
stress induced cardiac dilation and contractile dysfunction. Circulation, in press (Epub ahead of print).
Contact Information
- Antony Rodriguez, Ph.D.
- Department of Human and Molecular Genetics
- Baylor College of Medicine
- One Baylor Plaza, ABBR806
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-1980
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- E-mail: antonyr@bcm.edu
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