The recent (2008/2009) scientific activity of the group is focused on:

1) Analysis of the function of the Pik3cg (PI3K ) gene.
The aim of the project is to identify the role of PI3K, a cytoplasmic kinase involved in signal transduction triggered by seven transmembrane receptors. Our work established a role of this enzyme in inflammation, cardiac activity and respiratory function.

2) Identification and characterization of the effects of PI3K inhibition by selective drugs.
The aim of this study is to combine genetic and pharmacological data to model PI3K inhibition and to validate its effectiveness in the treatment of inflammatory diseases. These studies in collaboration with different companies, allowed the identification of compounds able to block rheumatoid arthritis in mice.

3) Analysis of the role of the Pik3cb (PI3K ) gene.
The aim of this study is to clarify the function of PI3K, a lipid kinase that is involved downstream both seven transmembrane and tyrosine kinase receptors. Our studies revealed that inactivation of PI3K causes a mild type 2 diabetes but a reduction in the development of Erbb2-positive mammary gland cancer.

Hirsch E., Iglesias A., Potocnik AJ., Hartmann U., Fässler R.
Impaired migration but not differentiation of haemopoietic stem cells in the absence of 1 integrins.
Nature. 380, 171-175. (1996).

Fässler R., Georges-Labuesse E., Hirsch E.
Genetic analysis of integrin function.
Current Opinion in cell Biology. 8, 641-646. (1996).

Hirsch E., Katanaev V. L., Garlanda C., Azzolino O., Pirola L., Silengo L., Sozzani S., Mantovani A., Altruda F., Wymann M.P.
Central Role for G Protein Coupled Phosphoinositide 3-Kinase  in Inflammation.
Science. 287 : 1049-1051 (2000).

Barbier M., Attoub S., Calvez R., Laffargue M., Mareel M., Altruda F., Christian G., Hirsch E., Wymann M.P.
Tumour biology. Weakening link to colorectal cancer?
Nature. 413 : 796 (2001).

Crackower M.A., Oudit G.Y., Kozieradzki I., Sarao R., Sun H., Sasaki T., Hirsch E., Suzuki A., Shioi T., Irie-Sasaki J., Sah R., Cheng H.M., Rybin V.O., Lembo G., Fratta L., Oliveira-dos-Santos A.J., Benovic J.L., C. Kahn R., Izumo S., Steinberg S.F., Wymann M.P., Backx P.H., Penninger J.M.
Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways.
Cell. 110 : 737-749 (2002).

Garlanda C.*, Hirsch E.*, Bozza S., Antonietta Salustri A., De Acetis M., Nota R., Alessia Maccagno, Riva F., Bottazzi B., Peri G., Doni A., Vago L., Botto M., De Santis R., Paolo Carminati, Siracusa G., Altruda F., Vecchi A., Romani L., Mantovani A.
* Authors contributed equally to the work.
Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response
Nature. 420 : 182-186 (2002).

Brancaccio M., Fratta L., Notte A, Hirsch E., Poulet R., Guazzone S., De Acetis M., Vecchione C., Marino G., Altruda F., Silengo L., Tarone G., Lembo G.
Melusin, a muscle-specific integrin beta(1)-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload.
Nature Medicine. 9 : 68-75 (2003).

Patrucco E., Notte A., Barberis L., Selvetella G., Maffei A., Brancaccio M., Marengo S., Russo G., Azzolino O., Rybalkin S., Silengo L., Altruda F., Wetzker R., Wymann M., Lembo G., Hirsch E.
PI3K modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and independent effects.
Cell. 118 : 375-387 (2004).

Vecchione C., Patrucco E., Gennaro M., Barberis L., Poulet R., Aretini A., Maffei A., Gentile M.T., Storto M., Azzolino O., Brancaccio M., Colussi G.L., Bettarini U., Altruda F., Silengo L., Tarone G., Wymann M.P., Hirsch E.*, Lembo G.*
* Authors contributed equally to the work.
Protection from Angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3K
Journal of Experimental Medicine. 201:1217-1228 (2005).

Camps M., Ruckle T., Ji H., Ardissone V., Rintelen F., Shaw J., Ferrandi C., Chabert C., Gillieron C., Francon B., Martin T., Gretener D., Perrin D., Leroy D., Vitte P.A., Hirsch E., Wymann M.P., Cirillo R., Schwarz M.K., Rommel C.
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.
Nature Medicine.11:936-943. (2005).

Ferguson G.J., Milne L., Kulkarni S., Sasaki T., Walker S., Andrews S., Crabbe T., Finan P., Jones G, Jackson S., Camps M., Rommel C., Wymann M., Hirsch E., Hawkins P., Stephens L.
PI(3)Kgamma has an important context-dependent role in neutrophil chemokinesis.
Nature Cell Biology. 9:86-91 (2007).

Costa C, Barberis L, Ambrogio C, Manazza AD, Patrucco E, Azzolino O, Neilsen PO, Ciraolo E, Altruda F, Prestwich GD, Chiarle R, Wymann M, Ridley A, Hirsch E.
Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase .
Proceedings of the National Academy of Sciences of the United States of America. 104:14354-14359 (2007).

Nombela-Arrieta C., Mempel T.R., Soriano S.F., Mazo I., Wymann M.P., Hirsch E., Martinez-A C., Fukui Y., von Andrian U.H., Stein JV.
A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress.
Journal Experimental Medicine. 204:497-510 (2007).

Costa C., Barberis L., Ambrogio C., Manazza A.D., Patrucco E., Azzolino O., Neilsen P.O., Ciraolo E., Altruda F., Prestwich G.D., Chiarle R., Wymann M., Ridley A., Hirsch E.
Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase .
Proceedings of the National Academy of Sciences of the United States of America. 104:14354-14359 (2007).

Alcázar I., Marqués M., Kumar A., Hirsch E., Wymann M., Carrera A.C., Barber D.F.
Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation.
Journal Experimental Medicine. 204:2977-2987. (2007).

Fougerat A., Gayral S., Gourdy P., Schambourg A., Rückle T., Schwarz M.K., Rommel C., Hirsch E., Arnal J.F., Salles J.P., Perret B., Breton-Douillon M., Wymann M.P., Laffargue M.
Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.
Circulation. 117:1310-1317. (2008).

Ciraolo E., Iezzi M., Marone R., Marengo S., Curcio C., Costa C., Azzolino O., Gonella C., Rubinetto C., Wu H., Dastrù W., Martin E.L., Silengo L., Altruda F., Turco E., Lanzetti L., Musiani P., Rückle T., Rommel C., Backer J.M., Forni G., Wymann M.P., Hirsch E.
Phosphoinositide -Kinase p110 activity: Key Role in Metabolism and Mammary Gland Cancer but not Development.
Science Signaling. 1(36):ra3. (2008).