Bio

Clinical Focus


  • Anesthesia

Academic Appointments


Honors & Awards


  • NIH K23, NIGMS (2014)
  • Kozaka research award, International Anesthesia Research Society (2013)
  • Stanford Society for Physician Scholar's award, SSPS (2011, 2012)
  • Albert J. Ryan Fellowship, Harvard Medical School (2004)
  • Carnot Foundation Scholarship, Ecole Polytechnique, Paris, France (2000)
  • George Lurcy's Fellowship, Harvard University (2000)

Professional Education


  • Board Certification: Anesthesia, American Board of Anesthesiology (2014)
  • Residency:Stanford University School of Medicine (2013) CA
  • Internship:Santa Clara Valley Medical Center (2010) CA
  • Medical Education:Harvard Medical School (2009) MA
  • PhD, Harvard Medical School, Neurobiology (2005)
  • BS, Ecole Polytechnique, Engineering (2000)

Patents


  • Brice Gaudilliere, Gabriela Fragiadakis, Martin Angst, Garry Nolan. "United States Patent S13-373 Flow cytometry methods for the diagnosis of prolonged convalescence after traumatic injury", Leland Stanford Junior University
  • Azad Bonni, Aryaman Shalizi, Brice Gaudilliere. "United StatesMethods and compositions for modulating synapse formation", Harvard University

Research & Scholarship

Current Research and Scholarly Interests


Our group studies how the human immune system responds to acute physiological perturbations, such as surgical trauma. Using high parameter single cell technologies (CyTOF) and proteomics approaches for the deep immune profiling of patients undergoing surgery, our research aims at identifying immune mechanisms (cell subsets and associated signaling pathways) that critically determine a patient's ability to heal and recover from surgical trauma.

Clinical Trials


  • Immune-modulation Effects of an Arginine Rich Nutritional Supplement in Surgical Patients Not Recruiting

    The primary objective of this study is to characterize the immune-modulatory effects of arginine-rich nutritional supplements in patients undergoing surgery. Numerical and functional changes of all circulating immune cells will be assessed with mass cytometry.

    Stanford is currently not accepting patients for this trial. For more information, please contact Julian Silva, MA, 650-724-9341.

    View full details

  • Detection of Immune Changes as a Result of Surgical Trauma in Human Subject Recruiting

    Surgical trauma triggers a massive inflammatory response. Over time, both the innate and adaptive branches of the immune system are affected by surgical trauma. The purpose of this study to characterize the cellular and molecular mechanisms immune response to surgical trauma. Additionally, detailed information about patients' recovery profile will be recorded over a period of 6 weeks, with the eventual goal of linking immune responses to recovery profiles.

    View full details

Publications

Journal Articles


  • Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining. Cytometry. Part A : the journal of the International Society for Analytical Cytology Behbehani, G. K., Thom, C., Zunder, E. R., Finck, R., Gaudilliere, B., Fragiadakis, G. K., Fantl, W. J., Nolan, G. P. 2014; 85 (12): 1011-1019

    Abstract

    Fluorescent cellular barcoding and mass-tag cellular barcoding are cytometric methods that enable high sample throughput, minimize inter-sample variation, and reduce reagent consumption. Previously employed barcoding protocols require that barcoding be performed after surface marker staining, complicating combining the technique with measurement of alcohol-sensitive surface epitopes. This report describes a method of barcoding fixed cells after a transient partial permeabilization with 0.02% saponin that results in efficient and consistent barcode staining with fluorescent or mass-tagged reagents while preserving surface marker staining. This approach simplifies barcoding protocols and allows direct comparison of surface marker staining of multiple samples without concern for variations in the antibody cocktail volume, antigen-antibody ratio, or machine sensitivity. Using this protocol, cellular barcoding can be used to reliably detect subtle differences in surface marker expression. © 2014 International Society for Advancement of Cytometry.

    View details for DOI 10.1002/cyto.a.22573

    View details for PubMedID 25274027

  • Clinical recovery from surgery correlates with single-cell immune signatures. Science translational medicine Gaudillière, B., Fragiadakis, G. K., Bruggner, R. V., Nicolau, M., Finck, R., Tingle, M., Silva, J., Ganio, E. A., Yeh, C. G., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Davis, M. M., Bendall, S. C., Fantl, W. J., Angst, M. S., Nolan, G. P. 2014; 6 (255): 255ra131

    Abstract

    Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.

    View details for DOI 10.1126/scitranslmed.3009701

    View details for PubMedID 25253674

  • A FOXO-Pak1 transcriptional pathway controls neuronal polarity GENES & DEVELOPMENT de la Torre-Ubieta, L., Gaudilliere, B., Yang, Y., Ikeuchi, Y., Yamada, T., DiBacco, S., Stegmueller, J., Schueller, U., Salih, D. A., Rowitch, D., Brunet, A., Bonni, A. 2010; 24 (8): 799-813

    Abstract

    Neuronal polarity is essential for normal brain development and function. However, cell-intrinsic mechanisms that govern the establishment of neuronal polarity remain to be identified. Here, we report that knockdown of endogenous FOXO proteins in hippocampal and cerebellar granule neurons, including in the rat cerebellar cortex in vivo, reveals a requirement for the FOXO transcription factors in the establishment of neuronal polarity. The FOXO transcription factors, including the brain-enriched protein FOXO6, play a critical role in axo-dendritic polarization of undifferentiated neurites, and hence in a switch from unpolarized to polarized neuronal morphology. We also identify the gene encoding the protein kinase Pak1, which acts locally in neuronal processes to induce polarity, as a critical direct target gene of the FOXO transcription factors. Knockdown of endogenous Pak1 phenocopies the effect of FOXO knockdown on neuronal polarity. Importantly, exogenous expression of Pak1 in the background of FOXO knockdown in both primary neurons and postnatal rat pups in vivo restores the polarized morphology of neurons. These findings define the FOXO proteins and Pak1 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal polarity, thus identifying a novel function for the FOXO transcription factors in a unique aspect of neural development.

    View details for DOI 10.1101/gad.1880510

    View details for Web of Science ID 000276730300008

    View details for PubMedID 20395366

  • PIASx is a MEF2 SUMO E3 ligase that promotes postsynaptic dendritic morphogenesis JOURNAL OF NEUROSCIENCE Shalizi, A., Bilimoria, P. M., Stegmueller, J., Gaudilliere, B., Yang, Y., Shuai, K., Bonni, A. 2007; 27 (37): 10037-10046

    Abstract

    Postsynaptic morphogenesis of dendrites is essential for the establishment of neural connectivity in the brain, but the mechanisms that govern postsynaptic dendritic differentiation remain poorly understood. Sumoylation of the transcription factor myocyte enhancer factor 2A (MEF2A) promotes the differentiation of postsynaptic granule neuron dendritic claws in the cerebellar cortex. Here, we identify the protein PIASx as a MEF2 SUMO E3 ligase that represses MEF2-dependent transcription in neurons. Gain-of-function and genetic knockdown experiments in rat cerebellar slices and in the postnatal cerebellum in vivo reveal that PIASx drives the differentiation of granule neuron dendritic claws in the cerebellar cortex. MEF2A knockdown suppresses PIASx-induced dendritic claw differentiation, and expression of sumoylated MEF2A reverses PIASx knockdown-induced loss of dendritic claws. These findings define the PIASx-MEF2 sumoylation signaling link as a key mechanism that orchestrates postsynaptic dendritic claw morphogenesis in the cerebellar cortex and suggest novel functions for SUMO E3 ligases in brain development and plasticity.

    View details for DOI 10.1523/JNEUROSCI.0361-07.2007

    View details for Web of Science ID 000249415000024

    View details for PubMedID 17855618

  • Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ramos, B., Gaudilliere, B., Bonni, A., Gill, G. 2007; 104 (23): 9882-9887

    Abstract

    Integration of inputs by a neuron depends on dendritic arborization patterns. In mammals, the genetic programs that regulate dynamic remodeling of dendrites during development and in response to activity are incompletely understood. Here we report that knockdown of the transcription factor Sp4 led to an increased number of highly branched dendrites during maturation of cerebellar granule neurons in dissociated cultures and in cerebellar cortex. Time-course analysis revealed that depletion of Sp4 led to persistent generation of dendritic branches and a failure in resorption of transient dendrites. Depolarization induced a reduction in the number of dendrites, and knockdown of Sp4 blocked depolarization-induced remodeling. Furthermore, overexpression of Sp4 wild type, but not a mutant lacking the DNA-binding domain, was sufficient to promote dendritic pruning in nondepolarizing conditions. These findings indicate that the transcription factor Sp4 controls dendritic patterning during cerebellar development by limiting branch formation and promoting activity-dependent pruning.

    View details for DOI 10.1073/pnas.0701946104

    View details for Web of Science ID 000247114100061

    View details for PubMedID 17535924

  • A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science Shalizi, A., Gaudillière, B., Yuan, Z., Stegmüller, J., Shirogane, T., Ge, Q., Tan, Y., Schulman, B., Harper, J. W., Bonni, A. 2006; 311 (5763): 1012-1017

    Abstract

    Postsynaptic differentiation of dendrites is an essential step in synapse formation. We report here a requirement for the transcription factor myocyte enhancer factor 2A (MEF2A) in the morphogenesis of postsynaptic granule neuron dendritic claws in the cerebellar cortex. A transcriptional repressor form of MEF2A that is sumoylated at lysine-403 promoted dendritic claw differentiation. Activity-dependent calcium signaling induced a calcineurin-mediated dephosphorylation of MEF2A at serine-408 and, thereby, promoted a switch from sumoylation to acetylation at lysine-403, which led to inhibition of dendritic claw differentiation. Our findings define a mechanism underlying postsynaptic differentiation that may modulate activity-dependent synapse development and plasticity in the brain.

    View details for PubMedID 16484498

  • A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis NEURON Gaudilliere, B., Konishi, Y., de la Iglesia, N., Yao, G. I., Bonni, A. 2004; 41 (2): 229-241

    Abstract

    The elaboration of dendrites is fundamental to the establishment of neuronal polarity and connectivity, but the mechanisms that underlie dendritic morphogenesis are poorly understood. We found that the genetic knockdown of the transcription factor NeuroD in primary granule neurons including in organotypic cerebellar slices profoundly impaired the generation and maintenance of dendrites while sparing the development of axons. We also found that NeuroD mediated neuronal activity-dependent dendritogenesis. The activity-induced protein kinase CaMKII catalyzed the phosphorylation of NeuroD at distinct sites, including endogenous NeuroD at Ser336 in primary neurons, and thereby stimulated dendritic growth. These findings uncover an essential function for NeuroD in granule neuron dendritic morphogenesis. Our study also defines the CaMKII-NeuroD signaling pathway as a novel mechanism underlying activity-regulated dendritic growth that may play important roles in the developing and mature brain.

    View details for Web of Science ID 000221457800009

    View details for PubMedID 14741104

  • Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern JOURNAL OF NEUROSCIENCE Shalizi, A., LEHTINEN, M., Gaudilliere, B., Donovan, N., Han, J. H., Konishi, Y., Bonni, A. 2003; 23 (19): 7326-7336

    Abstract

    The temporally specific nature of neurotrophic factor-induced responses is a general feature of mammalian nervous system development, the mechanisms of which remain to be elucidated. We characterized a mechanism underlying the temporal specificity by which BDNF selectively promotes the survival of newly generated, but not mature, granule neurons of the mammalian cerebellum. We found that BDNF specifically induces the extracellular signal-regulated kinase 5 (ERK5)-myocyte enhancer factor (MEF2) signaling pathway in newly generated granule neurons and thereby induces transcription of neurotrophin-3 (NT-3), a novel gene target of MEF2. Inhibition of endogenous ERK5, MEF2, or NT-3 in neurons by several approaches including disruption of the NT-3 gene in mice revealed a requirement for the ERK5-MEF2-NT-3 signaling pathway in BDNF-induced survival of newly generated granule neurons. These findings define a novel mechanism that underlies the antiapoptotic effect of neurotrophins in a temporally defined pattern in the developing mammalian brain.

    View details for Web of Science ID 000184817700011

    View details for PubMedID 12917366

  • RNA interference reveals a requirement for myocyte enhancer factor 2A in activity-dependent neuronal survival JOURNAL OF BIOLOGICAL CHEMISTRY Gaudilliere, B., Shi, Y., Bonni, A. 2002; 277 (48): 46442-46446

    Abstract

    RNA interference (RNAi) provides a powerful method of gene silencing in eukaryotic cells, including proliferating mammalian cells. However, the utility of RNAi as a method of gene knock-down in primary postmitotic mammalian neurons remained unknown. Here, we asked if RNAi might be utilized to allow the assessment of the biological function of a specific gene in the nervous system. We employed a U6 promoter-driven DNA template approach to induce hairpin RNA-triggered RNAi to characterize the role of the transcription factor myocyte enhancer factor 2A (MEF2A) in the neuronal activity-dependent survival of granule neurons of the developing rat cerebellum. We found that the expression of MEF2A hairpin RNAs leads to the efficient and specific inhibition of endogenous MEF2A protein expression in primary cerebellar granule neurons. We also found that RNAi of MEF2A reduces significantly MEF2 response element-mediated transcription in granule neurons and inhibits activity-dependent granule neuron survival. Taken together, our RNAi experiments have revealed that MEF2A plays a critical role in activity-dependent neuronal survival. In addition, our findings indicate that RNAi does operate in postmitotic mammalian neurons and thus offers a rapid genetic method of studying gene function in the development and function of the mammalian nervous system.

    View details for DOI 10.1074/jbc.M206653200

    View details for Web of Science ID 000179529300096

    View details for PubMedID 12235147

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