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Claudio G Giraudo, Ph.D.

Claudio G Giraudo, Ph.D.

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Assistant Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
The Children's Hospital of Philadelphia
Abramson Research Center, Room 816C
Philadelphia, PA 19104
Office: 267-425 –2124
Fax: 267-426-5165
Lab: 215-590-7302
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.
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Perelman School of Medicine > Faculty > Search

Description of Research Expertise

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

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.

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.

Lab Personnel:
Waldo A. Spessott (Postdoctoral Fellow)
Margaret McCormick (Research Technician)
Maria L. Sanmillan (Research Technician)
Vineet V. Kulkarni (CPM- Graduate Student)

Selected Publications

Waldo A. Spessott , Maria L. Sanmillan , Margaret E. McCormick , Nishant Patel , Joyce Villanueva, Kejian Zhang, Kim E. Nichols and Claudio G. Giraudo: Familial hemophagocytic lymphohistiocytosis caused by a novel dominant-negative mutation in STXBP2 that inhibits SNARE-mediated membrane fusion. Blood 125(10): 1566-77, March 2015.

Maria Shutova, Waldo A. Spessott, Claudio G. Giraudo, Tatyana Svitkina: Endogenous species of mammalian nonmuscle myosin IIA and IIB include activated monomers and heteropolymers. Current Biology 24(17): 1958-68, September 2014.

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.: Directing traffic into the future. Developmental Cell 27(5): 480-4, November 2013.

Shi L, Kümmel D, Melia TJ, Coleman J, Giraudo CG: Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Syntaxin 1 H3 domain and SNARE complex. Mol. Biol. Cell 22: 4150, November 2011.

Krishnakumar SS, Radoff DT, Kümmel D, Giraudo CG, Li F, Khandan L, Baguley SW, Coleman J, Reinisch KM, Pincet F, Rothman JE: A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion. Nat Struct Mol Biol. 18(8): 934-40, July 2011.

Kümmel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM: Complexin cross-links prefusion SNAREs into a zigzag array. Nat. Struct. Mol. Biol. 18(8): 927-33, July 2011.

Li F, Pincet F, Perez E, Giraudo CG, Tareste D, Rothman JE: Complexin activates and clamps SNAREpins by a common mechanism involving an intermediate energetic state. Nat Struct Mol Biol. 18(8): 941-6, July 2011.

Quinteros CA, Giraudo CG, Villareal M, Montich G and Maccioni HJ: Identificatification of a site in Sar1 involved in the interaction with the Cts of Glycolipid Glycosyltransferases. J. Biol. Chem 285: 30340-6, September 2010.

Giraudo CG, Garcia-Diaz A, Eng WS, Chen Y, Hendrickson W, Melia TJ, Rothman JE: Alternative zippering as an On-Off switch of SNARE-mediated membrane fusion. Science 323: 21211-21219, January 2009 Notes: Highlighted by Claudia Wiedemann: Membrane Dynamic: Clamping Complexin. Nature Reviews Molecular Cell Biology (2009) 10:160.

Giraudo CG, Garcia-Diaz A, Eng WS, Yamamoto A, Melia TJ, Rothman JE: Distinct domains of complexins bind SNARE complexes and clamp fusion in vitro. J Biol Chem 283: 21211-21219, July 2008.

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Last updated: 02/29/2016
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