It is well established that DARPP-32 is a key integrator of striatal signaling in physiological conditions as well as in the context of psychostimulants. Beside dopamine, various neurotransmitters such as glutamate act on and modify DARPP-32 downstream signaling. Our studies have demonstrated the importance of multiple signaling pathways converging on DARPP-32 in the action of drugs of abuse, and recently we have developed state-of-the-art technologies proving that these signaling events are specifically regulated in different sub-populations of medium spiny neurons (MSNs) that differentially express Dl and D2 types of dopamine receptor. Our ongoing research will focus on studies of mGluRS, an important GPCR invovled in glutamate-dependent DARPP-32 regulation, and two kinases, CKI and CK2. CKI is a crucial player in the mGluR5/DARPP-32 pathway and CK2 is essential for regulation of DARPP-32 nuclear trafficking. We have generated novel mouse lines for each of the three proposed Aims that will allow us not only to study the impact of psychostimulants in vivo but also to evaluate the relative importance of D1- and D2-MSNs in these phenomena. To address these questions we propose three Aims in Project 2 of the Program Project Grant.
In Aim I we will study the role of the newly discovered mGluRS regulator Norbin in the actions of psychostimulants.
In Aim II we will study the role of CK1 in the mGluRS/DARPP-32 pathway in vivo. We will also further charcterize the CK16 over expressing mice that present some behavioral features that ressembles ADHD. We will further address differences observed between Dl and D2 receptor pathways.
In Aim III we will study the role of CK2 in the actions of psychostimulants, in both Dl and D2-MSNs using specific KO strategies. Results from this Project will complement the other two Projects of this Program Project grant. In addition we will also carry out a number of collaborative studies with Projects 1 and 3, including studies involving spine morphology with Project 1 and phosphoproteomic studies and behavioral studies with Project 3.

Public Health Relevance

The proposed project will shed light on crucial regulatory steps that are strongly involved in striatal signaling and in the action of drugs of abuse. This work will increase our knowledge of psychostimulant-induced dysfunctions and might, by opening new possible therapeutic avenues, contribute to the development of small molecules that could counteract partially or totally the perverse effects of psychostimulants.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Center Core Grants (P30)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Tomescu, Costin; Tebas, Pablo; Montaner, Luis J (2017) IFN-? augments NK-mediated antibody-dependent cellular cytotoxicity (ADCC) of HIV-1 infected autologous CD4+ T cells regardless of MHC-I downregulation. AIDS :
Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417
Veglia, Filippo; Gabrilovich, Dmitry I (2017) Dendritic cells in cancer: the role revisited. Curr Opin Immunol 45:43-51
Hoffman, Hunter; Rice, Cory; Skordalakes, Emmanuel (2017) Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes. J Biol Chem 292:4593-4601
Lu, Fang; Wiedmer, Andreas; Martin, Kayla A et al. (2017) Coordinate Regulation of TET2 and EBNA2 Control DNA Methylation State of Latent Epstein-Barr Virus. J Virol :
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Lynch, Shannon M; Mitra, Nandita; Ravichandran, Krithika et al. (2017) Telomere Length and Neighborhood Circumstances: Evaluating Biological Response to Unfavorable Exposures. Cancer Epidemiol Biomarkers Prev 26:553-560
Perales-Puchalt, Alfredo; Svoronos, Nikolaos; Rutkowski, Melanie R et al. (2017) Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 23:441-453
Pestell, Timothy G; Jiao, Xuanmao; Kumar, Mukesh et al. (2017) Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth. Oncotarget 8:81754-81775
Noguchi, Shuhei; Arakawa, Takahiro; Fukuda, Shiro et al. (2017) FANTOM5 CAGE profiles of human and mouse samples. Sci Data 4:170112

Showing the most recent 10 out of 685 publications