PEOPLE

Claudio G. Giraudo, PhD

Assistant Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact InformationThe Children's Hospital of Philadelphia
Abramson Research Center, Room 816C
Philadelphia, PA 19104
Office: 267-425 –2124
Fax: 267-426-5165

Email: giraudoc@mail.med.upenn.edu

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Research Interest:
The research of the lab aims to understand how immune cells kill virus-infected cells and tumors

Keywords:
Cell Biology, Cytotoxic T-cells, Natural Killer cells, cell-mediated cytotoxicity, Primary Immune Deficiencies, HLH, Membrane Trafficking, Exocytosis, Membrane fusion, SNAREs.

Research Details:
Cytotoxic T-cells (CTLs) and Natural Killer (NK) cells are key components of the innate and adaptive immune system responsible to destroy virus-infected and cancer cells. CTL and NK cells perform this fundamental function by releasing apoptotic proteins contained within lytic granules at the contact area with a target cell known as Immunological Synapse. Patients with defects in these processes most commonly manifest with Familial Hemophagocytic Lymphohistiocytosis (FHL), a fulminant Primary Immunodeficiency characterized by a disproportionate deregulation of the immune system. In particular, my lab is interested in determine how gene mutations affect the molecular machinery that control the membrane fusion steps required for the cytotoxic immune response. By providing a better understanding of WT and mutant FHL-associated proteins, our studies will shed new light on the critical mechanisms that control cell-killing pathways in CTL and NK cells. To study how these processes are achieved we utilize multidisciplinary approaches including biochemical reconstitution, proteomics, biophysical analysis, live cell imaging and Total Internal Reflection Microscopy. In addition, we are developing novel simplified fusion assays that will help us to elucidate the molecular mechanism of how lytic granule exocytosis is controlled in time and space. In summary, our studies will contribute more broadly to our understanding of the membrane trafficking steps involved during a normal cell-mediated immune response, establish common and gene-specific pathways affected in wide range of genetic disorders that share some manifestations of HLH symptoms, aid in the development of new diagnostic tools and help in therapeutic decisions.

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Rotational Projects (2016-2017):
Test how FHL mutations in STXBP2 and MUNC13-4 affect SNARE-mediated fusion using reconstituted fusion assays
Study the effect of FHL mutations on the perforin-dependent and cell death receptor-dependent killing pathways.
Investigate by Super Resolution Microscopy (STED) the distribution patterns of fluorescently labeled SNAREs during the cytotoxic immune response.
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Lab Personnel:
Waldo A. Spessott (Postdoctoral Fellow)
Margaret McCormick (Research Technician)
Maria L. Sanmillan (Research Technician)
Vineet V. Kulkarni (CPM- Graduate Student)


Graduate Groups

Cell and Molecular Biology
Immunology

Education

B.A.. (Biochemist), National University of Cordoba - Argentina, 1996
M.S. (Chemistry), National University of Cordoba - Argentina, 1997
Ph.D. (Chemical Sciences), National University of Cordoba - Argentina, 2002

Specialty Certification

Postgraduate Training

Doctoral Fellow, Chemical Sciences, CIQUIBIC-CONICET, Centro de Investigaciones en Química Biologica, University of Cordoba - Argentina., 1998-2002
Postdoctoral Fellow, Biological Chemistry, CIQUIBIC-CONICET, Centro de Investigaciones en Química Biologica, National University of Cordoba - Argentina., 2002-2003
Postdoctoral Fellow, Cellular Biophysics and Biochemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA., 2003-2004
Postdoctoral Research Scientist, Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., 2004-2006

Awards and Honors

Doctoral Fellowship from Consejo de Investigaciones Cientificas y Tecnologicas de la Provincia de Cordoba, Argentina (CONICOR)., 1996
Doctoral Fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (CONICET)., 1998
VI Bernardo A. Houssay Award of the Argentinean Society of Biology., 2000
Postdoctoral Fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (CONICET)., 2002
PEW Scholar in Biomedical Sciences - The PEW Charitable Trusts, 2013
W.W. Smith Scholar / W.W. Smith Charitable Trust, 2015
Histiocyte Society Award / Histiocyte Society, 2016

Memberships and Professional Organizations

American Society of Cell Biology, 2003 - Present
Histiocyte Society, 2013 - Present
American Association for Immunologist, 2013 - Present

Web Links


Selected Publications

Munc18-2 facilitates transition for Syntaxin 11-mediated hemifusion to complete fusion for T-lymphocyte cytotoxicity

2. Waldo A. Spessott , Maria L. Sanmillan , Margaret E. McCormick , Vineet K.Kulkarni and Claudio G. Giraudo., P.N.A.S. In press(): , 2017

Familial hemophagocytic lymphohistiocytosis caused by a novel dominant-negative mutation in STXBP2 that inhibits SNARE-mediated membrane fusion

Waldo A. Spessott , Maria L. Sanmillan , Margaret E. McCormick , Nishant Patel , Joyce Villanueva, Kejian Zhang, Kim E. Nichols and Claudio G. Giraudo, Blood 125(10): 1566-77, 2015, PMID:25564401

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Endogenous species of mammalian nonmuscle myosin IIA and IIB include activated monomers and heteropolymers

Maria Shutova, Waldo A. Spessott, Claudio G. Giraudo, Tatyana Svitkina, Current Biology 24(17): 1958-68, 2014, PMID:25131674

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Directing traffic into the future

Antonny B, Audhya J, l Bagnat M, von Blume J, Briggs JA, Giraudo C, Kaeser PS, Miller E, Reinisch K, Sbalzarini IF, Schuldiner M, Shen J, Takamori S, Verstreken P, Walther T., Developmental Cell 27(5): 480-4, 2013, PMID:24482802

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Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Syntaxin 1 H3 domain and SNARE complex.

Shi L, Kümmel D, Melia TJ, Coleman J, Giraudo CG, Mol. Biol. Cell 22(): 4150, 2011

A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion.

Krishnakumar SS, Radoff DT, Kümmel D, Giraudo CG, Li F, Khandan L, Baguley SW, Coleman J, Reinisch KM, Pincet F, Rothman JE, Nat Struct Mol Biol. 18(8): 934-40, 2011

Complexin cross-links prefusion SNAREs into a zigzag array.

Kümmel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM, Nat. Struct. Mol. Biol. 18(8): 927-33, 2011

Complexin activates and clamps SNAREpins by a common mechanism involving an intermediate energetic state

Li F, Pincet F, Perez E, Giraudo CG, Tareste D, Rothman JE, Nat Struct Mol Biol. 18(8): 941-6, 2011

Identificatification of a site in Sar1 involved in the interaction with the Cts of Glycolipid Glycosyltransferases.

Quinteros CA, Giraudo CG, Villareal M, Montich G and Maccioni HJ, J. Biol. Chem 285(): 30340-6, 2010

Alternative zippering as an On-Off switch of SNARE-mediated membrane fusion.

Giraudo CG, Garcia-Diaz A, Eng WS, Chen Y, Hendrickson W, Melia TJ, Rothman JE, Science 323(): 21211-21219, 2009