Bio

Bio


Dr. Rojas-Muñoz is an Instructor affiliated to the Cardiovascular Institute at the Stanford School of Medicine. He obtained his PhD in Genetics in 2005 under the direction of the Nobel Laureate Dr. Christiane Nüsslein-Volhard at the Max Planck Institute for Developmental Biology in Tübingen, Germany, where he generated, mapped and characterized genetic mutations affecting vertebrate eye development using zebrafish as a model system. Later, he continued his training at the Salk Institute in La Jolla under the direction of Dr. Juan Carlos Izpisúa-Belmonte, implementing the use of small compounds together with forward genetics to study epimorphic regeneration. In 2008 Dr. Rojas-Muñoz joined the Sanford-Burnham Medical Research Institute (SBMRI) where he participated in the development of a research program focused in the physiology of the cardiovascular system in vertebrates and established an assay development and screening unit within the Conrad Prebys Center for Chemical Genomics (CPCCG). Under his operation, the use of miRNA screening coupled with target identification and systems analysis was successful in revealing cellular signaling pathways and proteins that regulate myocardial physiology and protection. Most recently, his research efforts in characterizing the effect of miR-25 inhibition on cardiac function have been highlighted in Nature. Before joining Stanford Dr. Rojas-Muñoz was appointed Assistant Project Scientist in the Bioengineering department at the University of California San Diego. Building on his previous experience, Dr. Rojas-Muñoz’s long term goal is to use an integrated approach to understand the functions of miRNAs in cardiovascular biology and disease.

Academic Appointments


Professional Education


  • Dr. rer. nat., Tubingen University, Genetics (2005)

Patents


  • Agustin Rojas-Munoz, Christine Wahlquist, Mark Mercola, A Colas, Roger J. Hajjar, Dongtak Jeong. "United States Patent 20140243387 Methods for improving cardiac contractility", Sanford-Burnham Medical Reserach Institute, Icahn School of Medicine at Mount Sinai, Aug 28, 2014

Research & Scholarship

Current Research and Scholarly Interests


Heart failure is a major cause of death worldwide. Up to 50% of these heart failure patients die from arrhythmias and sudden cardiac death (SCD). An intriguing aspect of SCD, however, is that affected individuals exhibit varied susceptibility to arrhythmogenic events, making risk stratification and prevention challenging. The overarching goal of Dr. Rojas-Muñoz's research is to uncover new molecular mediators of disease and use this information to develop novel diagnostic and therapeutic modalities for SCD. Human-induced Pluripotent Stem Cells-derived Cardiomyocytes (hiPSC-CMs) offers an unprecedented opportunity to model arrhythmia mechanisms and link them to disease susceptibility and disease progression. Therefore, Dr. Rojas-Muñoz's current approach leverages the use hiPSC-CMs to define the molecular components that mediate the alteration of cardiac currents upon cardiomyocyte stress and test for their ability to alter disease manifestation in patient specific models of long QT syndrome (LQTS) and in animal models of arrhythmia. Results from Dr. Rojas-Muñoz's research will provide a clearer picture of the circuit inducing and maintaining lethal arrhythmias, potentially leading to new strategies to lower morbidity and mortality of individuals at risk of SCD.

Publications

All Publications


  • Mechanosensitive miR-376c Modulates Arrhythmia Susceptibility Via Regulation Of KCNJ2 In hiPSC-derived Cardiomyocytes Wahlquist, C. A., Rojas-Munoz, A., Brunyeel, A. A., Greenhaw, M., Chung, R., Vu, M., Karakikes, I., Mercola, M. LIPPINCOTT WILLIAMS & WILKINS. 2018: E79
  • Integrating omics into the cardiac differentiation of human pluripotent stem cells WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE Rojas-Munoz, A., Maurya, M. R., Lo, F., Willems, E. 2014; 6 (4): 247–64

    Abstract

    Time-dependent extracellular manipulations of human pluripotent stem cells can yield as much as 90% pure populations of cardiomyocytes. While the extracellular control of differentiation generally entails dynamic regulation of well-known pathways such as Wnt, BMP, and Nodal signaling, the underlying genetic networks are far more complex and are poorly understood. Notably, the identification of these networks holds promise for understanding heart disease and regeneration. The availability of genome-wide experimentation, such as RNA and DNA sequencing, as well as high throughput surveying with small molecule and small interfering RNA libraries, now enables us to map the genetic interactions underlying cardiac differentiation on a global scale. Initial studies demonstrate the complexity of the genetic regulation of cardiac differentiation, exposing unanticipated novel mechanisms. However, the large datasets generated tend to be overwhelming and systematic approaches are needed to process the vast amount of data to improve our mechanistic understanding of the complex biology. Systems biology methods spur high hopes for parsing vast amounts of data into genetic interaction models that can be verified experimentally and ultimately yield functional networks that expose the genetic connections underlying biological processes.

    View details for DOI 10.1002/wsbm.1268

    View details for Web of Science ID 000337975900002

    View details for PubMedID 24753373

  • Inhibition of miR-25 improves cardiac contractility in the failing heart NATURE Wahlquist, C., Jeong, D., Rojas-Munoz, A., Kho, C., Lee, A., Mitsuyama, S., Van Mil, A., Park, W. J., Sluijter, J. P., Doevendans, P. A., Hajjar, R. J., Mercola, M. 2014; 508 (7497): 531-?

    Abstract

    Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.

    View details for DOI 10.1038/nature13073

    View details for Web of Science ID 000334741600038

    View details for PubMedID 24670661

    View details for PubMedCentralID PMC4131725

  • HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles GENES & DEVELOPMENT Saccone, V., Consalvi, S., Giordani, L., Mozzetta, C., Barozzi, I., Sandona, M., Ryan, T., Rojas-Munoz, A., Madaro, L., Fasanaro, P., Borsellino, G., De Bardi, M., Frige, G., Termanini, A., Sun, X., Rossant, J., Bruneau, B. G., Mercola, M., Minucci, S., Puri, P. L. 2014; 28 (8): 841-857

    Abstract

    Fibro-adipogenic progenitors (FAPs) are important components of the skeletal muscle regenerative environment. Whether FAPs support muscle regeneration or promote fibro-adipogenic degeneration is emerging as a key determinant in the pathogenesis of muscular diseases, including Duchenne muscular dystrophy (DMD). However, the molecular mechanism that controls FAP lineage commitment and activity is currently unknown. We show here that an HDAC-myomiR-BAF60 variant network regulates the fate of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray, genome-wide chromatin remodeling by nuclease accessibility (NA) combined with next-generation sequencing (NA-seq), small RNA sequencing (RNA-seq), and microRNA (miR) high-throughput screening (HTS) against SWI/SNF BAF60 variants revealed that HDAC inhibitors (HDACis) derepress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease. Specifically, HDAC inhibition induces two core components of the myogenic transcriptional machinery, MYOD and BAF60C, and up-regulates the myogenic miRs (myomiRs) (miR-1.2, miR-133, and miR-206), which target the alternative BAF60 variants BAF60A and BAF60B, ultimately directing promyogenic differentiation while suppressing the fibro-adipogenic phenotype. In contrast, FAPs from late stage dystrophic muscles are resistant to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the promyogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bipotency by epigenetic intervention with HDACis provides a molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles.

    View details for DOI 10.1101/gad.234468.113

    View details for Web of Science ID 000334585400005

    View details for PubMedID 24682306

    View details for PubMedCentralID PMC4003277

  • ErbB2 and ErbB3 regulate amputation-induced proliferation and migration during vertebrate regeneration DEVELOPMENTAL BIOLOGY Rojas-Munoz, A., Rajadhyksha, S., Gilmour, D., van Bebber, F., Antos, C., Rodriguez Esteban, C., Nuesslein-Volhard, C., Izpisua Belmonte, J. 2009; 327 (1): 177–90

    Abstract

    Epimorphic regeneration is a unique and complex instance of postembryonic growth observed in certain metazoans that is usually triggered by severe injury [Akimenko et al., 2003; Alvarado and Tsonis, 2006; Brockes, 1997; Endo et al., 2004]. Cell division and migration are two fundamental biological processes required for supplying replacement cells during regeneration [Endo et al., 2004; Slack, 2007]. However, the connection between the early stimuli generated after injury and the signals regulating proliferation and migration during regeneration remain largely unknown. Here we show that the oncogenes ErbB2 and ErbB3, two members of the EGFR family, are essential for mounting a successful regeneration response in vertebrates. Importantly, amputation-induced progenitor proliferation and migration are significantly reduced upon genetic and/or chemical modulation of ErbB function. Moreover, we also found that NRG1 and PI3K functionally interact with ErbB2 and ErbB3 during regeneration and interfering with their function also abrogates the capacity of progenitor cells to regenerate lost structures upon amputation. Our findings suggest that ErbB, PI3K and NRG1 are components of a permissive switch for migration and proliferation continuously acting across the amputated fin from early stages of vertebrate regeneration onwards that regulate the expression of the transcription factors lef1 and msxB.

    View details for DOI 10.1016/j.ydbio.2008.12.012

    View details for Web of Science ID 000263706200017

    View details for PubMedID 19133254

  • Bioelectricity and epimorphic regeneration BIOESSAYS Stewart, S., Rojas-Munoz, A., Izpisua Belmonte, J. 2007; 29 (11): 1133–37

    Abstract

    All cells have electric potentials across their membranes, but is there really compelling evidence to think that such potentials are used as instructional cues in developmental biology? Numerous reports indicate that, in fact, steady, weak bioelectric fields are observed throughout biology and function during diverse biological processes, including development. Bioelectric fields, generated upon amputation, are also likely to play a key role during vertebrate regeneration by providing the instructive cues needed to direct migrating cells to form a wound epithelium, a structure unique to regenerating animals. However, mechanistic insight is still sorely lacking in the field. What are the genes required for bioelectric-dependent cell migration during regeneration? The power of genetics combined with the use of zebrafish offers the best opportunity for unbiased identification of the molecular players in bioelectricity.

    View details for DOI 10.1002/bies.20656

    View details for Web of Science ID 000250661300009

    View details for PubMedID 17935197

  • chokh/rx3 specifies the retinal pigment epithelium fate independently of eye morphogenesis DEVELOPMENTAL BIOLOGY Rojas-Munoz, A., Dahm, R., Nusslein-Volhard, C. 2005; 288 (2): 348–62

    Abstract

    Despite the importance of the retinal pigment epithelium (RPE) for vision, the molecular processes involved in its specification are poorly understood. We identified two new mutant alleles for the zebrafish gene chokh (chk), which display a reduction or absence of the RPE. Unexpectedly, the neural retina (NR) in chk is specified and laminated, indicating that the regulatory network leading to NR development is largely independent of the RPE. Genetic mapping and molecular characterization revealed that chk encodes Rx3. Expression analyses show that otx2 and mitfb are not expressed in the prospective RPE of chk, indicating that the retinal homeobox gene rx3 acts upstream of the molecular network controlling RPE specification. Cellular transplantations demonstrate that rx3 function is autonomously required to specify the prospective RPE. Though rx2 is also absent in chk, neither rx2 nor rx1 is required for RPE development. Thus, our data provide the first indication that, in addition to controlling optic lobe evagination and proliferation, chk/rx3 also determines cellular fate.

    View details for DOI 10.1016/j.ydbio.2005.08.046

    View details for Web of Science ID 000234455900004

    View details for PubMedID 16300752