Ruggero Pardi
Ruggero Pardi
affiliation: Università Vita-Salute San Raffaele
research area(s): Immunity And Infection, Cancer Biology
  • Cell and Molecular Biology
  • Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele

University of Milan 1980 MD
University of Milan 1983 Sub-specialty in Pulmonary diseases
Stanford university 1985-1988 Post-doctoral fellow, Immunology
Yale University 1989-1991 Post-doctoral fellow, Immunobiology

Scientific & professional profile

Ruggero Pardi is an internationally recognized investigator in the field of integrin biology, and has devoted his scientific career to the study of the pathophysiology of adhesive interactions in the immune system and in the pathogenesis of cancer.

He has obtained his MD and Specialy Degree in Pneumology at the University of Milan in 1980 and 1983, respectively. In 1985 he moved as a post-doctoral fellow to the Department of Pathology, Stanford University School of Medicine, in the group led by E. G. Engleman. Between 1985 and 1988 Pardi and JR Bender (at the time a Cardiology Fellow at Stanford) pioneered the field of leukocyte-endothelial cell interactions, and were among the first to characterize the cell subsets and molecules involved in the adhesive interactions of various leukocyte subsets with primary microvascular endothelium (J. Clin. Invest. 1987. 79:1679). Between 1989 and 1991, Pardi and Bender relocated to Yale University, where Bender was appointed as Assistant Professor in the Department of Internal Medicine. Soon thereafter they showed that the leukocyte integrin LFA-1 undergoes regulated activation by engagement of the T Cell Receptor, involving the dynamic association with peripheral proteins of the actin cytoskeleton (JCB. 1992. 116:1211).

In 1991 R. Pardi was appointed as Assistant Professor at the Internal Medicine Department of the University of Milan School of Medicine. During such period he was among the first to demonstrate that ligand-engaged leukocyte integrins are competent to transduce intracellular signals (J. Immunol. 1989. 143:3157; PNAS. 1994. 91:3994; J. Cell Biol. 1995. 128:969) that involve breakdown of phosphoinositides and the establishment of transient interactions of the adhesion receptor with the actin-based cytoskeleton (J. Immunol. 1995. 155:1252) and lead to the regulation of gene expression programs in T cells (J. Clin Invest 1996. 98:1133; J. Immunol. 1999. 162: 1085; Eur J. Immunol. 2000. 30:136). His work also established that integrin turnover, entailing the regulated internalization and recycling of the adhesion receptor via defined endocytic sequences, is required to support vectorial motility of leukocytes (EMBO J. 1999. 18: 4915; Mol Biol Cell. 2003. 14:2570; Mol Biol. Cell. 2005. 16:5793)

More recently, Pardi's group has identified and fully chracterized at the genetic and functional level novel intermediates in integrin-generated signals leading to the control of gene expression programs (Nature 2000. 404:617) that are dysregulated in precancerous lesions (Oncogene 2008. 27:2401; J. Exp Med. 2008. 205:465)

In 2000 Pardi was appointed as Associate Professor of Pathology at the San Raffaele University School of Medicine and in 2007 he was promoted to Full Professor with tenure. He is teaching a 120 hour general pathology class to third year medical students and a 20 hour molecular oncology class to biotechnology MS students.

His most recent work concerns the demonstration that cooperative and concurrent signaling by chemokines and integrins is crucial to the coordination of the various steps of leukocyte extravasation (Blood. 2009. 114:1073; Blood. 2009. 113:1699; J. Cell Sci. 2009. 122: 268)

In the last 20 years Pardi has been awarded numerous grants from national and international funding agencies, and has coordinated several EU-funded networks, including a FP6 Network of Excellence (MAIN: composed of 16 Institutes from 8 EU and associated Countries, focusing on inflammatory Cell migration. From 2003 to 2007 he served as Dean of the Graduate School of Molecular Medicine of San Raffaele University. In 2008 he was named Chairman of the Division of Immunology, Transplantation and Infectious Diseases of the Scientific Institute San Raffaele. Overall, he has authored over 80 publications in international peer-reviewed journals, with a global impact factor exceeding 600. He has been invited as a speaker to over 25 international meetings in the last 15 years.
Our main scientific interest is the dissection of how adhesive interactions control the onset and maintenance of complex biological responses in multicellular organisms, and how dysregulation of such responses contributes to the pathogenesis of major diseases, such as cancer and chronic inflammatory diseases. We focus on the role of adhesion receptors in cell proliferation, survival and migration.

Adhesion receptor signaling and cell growth.

Most somatic cells require adhesion to substrate for progression through the cell cycle and the onset of DNA replication in response to growth factors. This phenomenon is known as "anchorage-dependence" (AD), and is thought to be largely dependent on active signaling by surface integrins, a highly conserved family of adhesion receptors involved in cell-extracellular matrix, as well as cell-cell adhesion. Numerous studies have unveiled the existence of a close relationship between loss of AD and tumorigenicity, by showing that the requirement for integrin-generated signals becomes less pronounced with increasing degrees of cell transformation. As integrins are devoid of catalytic function, we hypothesized that they transduce signals by dynamic, ligand-induced association with intracellular adaptors and effector molecules. We have recently identified a multimolecular protein complex, the COP9 signalosome (CSN), which appears to act as a point of convergence of signals originated from adhesion receptors and conveyed to the nucleus via post-translational modifications of selected transcriptional regulators involved in cell proliferation, differentiation and the adaptive response to stress. The CSN acts by regulating the function of defined classes of ubiquitin ligases, namely the Cullin-based ligase complexes, whose substrates are prominent effectors of cell cycle progression, survival and the DNA damage response. As the CSN is commonly amplified in cancer, we are currently investigating this novel signaling axis within the context of normal developmental processes and in neoplastic transformation. To this aim we have generated conditional knockout mice in which the catalytic subunit of the CSN has been genetically inactivated in various tissues.

Adhesion receptor dynamics in cell migration.

Cell migration implies the existence of mechanisms that move adhesion receptors from the cell rear toward the cell front, where they are available to form new protrusions and adhesions. Likewise, molecular signaling pathways involved in cell adhesion and migration become asymmetrically distributed in migrating cells, as a consequence of early signals originating from membrane receptors responding to migratory cues. We are currently investigating how chemokine-driven signals converge on modulating adhesion receptor dynamics during cell adhesion, polarization and directional migration. To this aim we have established a fundamental role of G protein-coupled receptor associated arresting as scaffolds catalyizing the assembly of molecular complexes that control the spatial and temporal regulation of integrin function. We are exploring such process using genetic, functional and molecular approaches both in mammalian cells, including mouse embryonic stem cells, and in the verterbate model organism Orizyia Latipes.
Jiange Zhang, Yasha Modi, Timur Yarovinsky, Jun Yu, Mark Collinge, Themis Kyriakides, Yizhun Zhu, William C. Sessa, Ruggero Pardi, and Jeffrey R. Bender. Macrophage Beta-2 Integrin-mediated, HuR-dependent Stabilization of Angiogenic Factor encoding mRNAs in Inflammatory Angiogenesis. 2011. PNAS. Under Revision

Deng, Z., Wei, N., Miller, D. Mountz, J. D., Pardi, R., Huang-ge, Z. Plant Homologue Constitutive photomorphogenesis 9 (COP9) signalosome regulates innate immune responses in experimental sepsis. 2011. Blood. In press.

B cell development and germinal center formation are JAB1 dependent. Selina Sitte, Julia Jellusova, Florian Weisel, Joachim Gläsner, Martina Panattoni, Ruggero Pardi, and André Gessner. 2011. J. Immunol. In press.

V. S. Ramgolam, S. D. DeGregorio, G. Rao, M. Collinge, S. S. Subaran, S. Markovic-Plese, R. Pardi and J. R. Bender. LFA-1 Engagement Induces HuR-dependent Cytokine mRNA Stabilization Through a Vav-1, Rac1/2, p38 and MKK3 Signaling Cascade. 2010. PloS One. 5:14450-14456.

M Penzo, R Molteni, T Suda, S Samaniego, RR Kew, H Jang, J, Li, R Pardi, ME Bianchi, KB Marcu. Inhibitor of NK-kB Kinases alpha and beta Are Both Essential for High Mobility Group Box 1-Mediated Chemotaxis. J Immunol. 2010. 184:4497-4509.

R. Molteni, C. Lage-Crespo, S. Feigelson, C. Moser, M. Fabbri, F. Krombach, R. Alon and R. Pardi. β-Arrestins Are Required For The Induction And Strengthening Of Shear-Stress Resistant Adhesion During Leukocyte Extravasation. Blood 2009. 114:1073-1082.

Panattoni M, Sanvito F, Basso V, Doglioni C, Montini E, Bender Jr, Mondino A, Pardi R.. Targeted Inactivation Of The Cop9 Signalosome Impairs Multiple Stages Of T Cell Development. Journal of Experimental Medicine. 2008. 205:465-477.

Savio MG, Rotondo G, Maglie S, Rossetti G, Bender JR, Pardi R. (In Stampa). Cop1D, An Alternatively Spliced Constitutive Photomorphogenetic-1 (COP1) Product, Stabilizes UV Stress-Induced C-Jun Through Inhibition Of Full Length COP1. Oncogene. 2008. 27: 2401-2411.

R. Molteni, M. Fabbri, J. R. Bender and R. Pardi. Pathophysiology of Leukocyte-Tissue Interactions. Curr. Op. Cell Biol. 2006. 18: 491-498

H. de la Fuente, M. Mittelbrunn, L. Sánchez-Martín, M. Vicente-Manzanares, A. Lamana, R. Pardi, C. Cabañas and F. Sánchez-Madrid. Synaptic clusters of MHC class II molecules induced on DCs by adhesion molecules-mediated initial T cell scanning. Mol. Biol. Cell. 2005. 16:3314-3322.

M. Fabbri, S. di Meglio, M. C. Gagliani, J. R. Bender, C. Tacchetti and R. Pardi Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the aL/b2 integrin (LFA-1) during leukocyte chemotaxis Mol. Biol. Cell. 2005. 16: 5793-5803.

E. Bianchi, S. Denti, A. Granata, J. Geginat, L. Rogge and R. Pardi. The integrin LFA-1 interacts with the transcriptional coactivator JAB1 to modulate AP-1 transcriprional activity. Nature. 404: 617-621, 2000.
Project Title:
Targeting myeloid cell migration in nonresolving inflammation
Chemokine-driven leukocyte extravasation and tissue infiltration are key events in inflammatory responses. The usual outcome of such responses is protection from the spread of infection, followed by resolution. There are however instances in which deregulated or persistent tissue infiltration by inflammatory cells contribute to disease progression, through extensive tissue damage, more than the pathogen itself. In diseases as diverse as atherosclerosis, rheumatoid arthritis, asthma, chronic hepatitis, inflammatory bowel disease and psoriasis, a variety of "inputs", both exogenous and endogenous, ultimately affect the recruitment and activation of immune and inflammatory cells, thereby amplifying and perpetuating the inflammatory state. The overall aim of this project is to address the role of beta-arrestin-dependent signaling in the concurrent steps of chemokine-driven leukocyte extravasation and interstitial migration. Based on our prior work and more recent findings we hypothesize that the dynamics of beta arrestin recruitment and its scaffolding function may vary depending on the chemokine ligand-receptor pair involved and its residency time in endocytic compartments, explaining in part the specificity of otherwise redundant signaling pathways elicited by different chemokines within the inflammatory milieu. The project will be developed by combining ex vivo (flow chamber assays) and in vivo (bone marrow reconstitution and intravital microscopy) approaches with genetic engineering aimed at dissecting the role of beta arrestins in chemokine-driven myeloid cell extravasation and tissue infiltration. The signaling network to be investigated controls the sustained activation of adhesion receptors in extravasating leukocytes. Most of the above molecules can be targeted by FDA-approved drugs, which we aim to test in our pre-clinical models as a proof of concept for their therapeutic use in nonresolving inflammatory conditions in human patients.

Project Title:
Role of the COP9 signalosome in oncogene-induced responses
The multi-molecular complex named the "COP9 signalosome" (CSN) is strictly conserved in vertebrates including mammals. Compelling genetic evidence, including recent findings from our group suggests that the CSN is an upstream, positive regulator ubiquitin ligase complexes in vivo, whose substrates regulate major signaling pathways and essential checkpoints in cell cycle progression as well as in the response to DNA damage. The CSN is overexpressed or amplified in a variety of cancers. Our prior findings and current evidence in mice carrying a conditional inactivation of the CSN5/JAB1 gene in T cells and hepatocytes indicate that the CSN coordinately regulates the c-Myc and p53 pathways to allow cell proliferation and survival under homeostatic conditions or following various types of stress. By using a combination of genetic, biochemical and functional approaches, we will assess the impact of CSN inactivation on tumorigenesis induced by deregulation of the c-Myc and p53 pathways. Genetic evidence for the functional regulation of the above signaling pathways by the CSN will be obtained either by acute overexpression of c-Myc using in vivo delivery by viral vectors or by crossing conditional CSN5del/del mice onto genetic backgrounds featuring inactivation of the p53 and CDKN2a genes. In parallel, in a c-Myc-initiated multiple myeloma mouse model, we will test the hypothesis that genetic or functional inactivation of the CSN might synergize with proteasome inhibitors to prevent tumor progression by altering the stability, polyubiquitination level and ultimately the function of substrates, including c-Myc and p53, which play an established pathogenic role in this class of tumors. We plan to test this hypothesis genetically, by crossing Vk*Myc mice with CSN5 floxed mice carrying a B cell specific tamoxifen-inducible Cre (LC-1-hCD19-CreERT2).