Systemic lupus erythematosus (SLE) is an autoimmune disorder of unknown etiology characterized by diverse T cell effector dysfunction. Interleukin-2 (IL-2) production is decreased in patients with SLE and lupus-prone mice and this contributes to the immunopathogenesis of the disease. This proposal is based on published and preliminary data which demonstrate that anti-CD3/TCR antibodies present in the sera of patients with SLE cause translocation of Calcium/calmodulin kinase 4 (CaMK4) from the cytoplasm to the nucleus where it suppresses IL-2 production. In the lupus prone MRL.lpr lupus-prone mouse, pharmacologic inhibition or genetic deletion of CaMK4 with a small drug inhibitor suppresses autoimmunity, mesangial cell proliferation and lupus nephritis. In additional data, CaMK4 appears to be involved in the generation of regulatory T cells. Based on these data we hypothesize that the ser/thr kinase CaMK4 contributes to the expression of autoimmunity by suppressing IL-2 production and Treg function and to the development of lupus nephritis by promoting mesangial cell proliferation. First, we will establish that CaMK4 translocates to the nucleus of SLE T cells, determine how it becomes activated and how it affects immunoregulation. Second, we will establish whether CaMK4 expressed in mesangial cells is independently responsible for excessive proliferation and the development of lupus nephritis. And, third, we plan to use nanolipogels loaded with an inhibitor of CaMK4 and tagged with antibodies to deliver the drug to T and mesangial cells. To carry out the studies we will use cells from patients with SLE and a newly constructed MRL.lpr mouse which lacks CaMK4 and nanolipogel technology to delver the CaMK4 inhibitor. The proposal identifies a new Ser/Thr kinase, CaMK4, in the regulation/dysregulation of the immune response and proliferation of mesangial cells and proposes the use of a novel nanolipogel delivery system to target a small drug inhibitor of CaMK4 to T and mesangial cells. The significance of the proposed work lies with the fact that it presents a novel target for the treatment of SLE and that it develops a targeted delivery of a small drug.

Public Health Relevance

Lupus afflicts more than one million Americans who are mostly women and young. Because of a number of limitations a clinically useful drug is still missing. Through this project we plan to develop a small drug inhibitor of a kinase deliverable in an organ targeted fashion for the treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR064350-01
Application #
8480535
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$376,236
Indirect Cost
$141,525
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya et al. (2014) KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3? regulatory T cells in MRL/lpr mice. Autoimmunity 47:445-50
Look, Michael; Saltzman, W Mark; Craft, Joe et al. (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35:1089-95
Sehgal, Kartik; Ragheb, Ragy; Fahmy, Tarek M et al. (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk. J Immunol 193:2297-305
Koga, Tomohiro; Hedrich, Christian M; Mizui, Masayuki et al. (2014) CaMK4-dependent activation of AKT/mTOR and CREM-? underlies autoimmunity-associated Th17 imbalance. J Clin Invest 124:2234-45
Grammatikos, Alexandros P; Kyttaris, Vasileios C; Kis-Toth, Katalin et al. (2014) A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus. Clin Immunol 150:192-200