Science Teams Against Disease

Science Teams Against Disease or STAD-Schizophrenia is a fund under The Community Foundation based in the state of Virginia, USA. It aims to attract philanthropic support from all over the world to enable a team of researchers from across the US to discover new treatments for Schizophrenia. This project is based on the discovery that two of the target receptors for antipsychotic drugs come together to form a complex with unique signaling properties.

Research

In 2008, a Nature paper by Gonzalez-Maeso and colleagues (Icahn School of Medicine at Mount Sinai) reported that two G protein-coupled receptors (GPCRs) that are targeted by antipsychotic drugs, the serotonin 5-HT2AR and the glutamate mGlu2R receptors, come together to form a complex that is deregulated in schizophrenic patients.^[1] The functional consequences of this interaction were revealed in the 2011 Cell paper from Logothetis lab (Virginia Commonwealth University) in which this heteromeric complex was shown to be a convergent site for the activity of anti- or propsychotic drugs.^[2] According to the authors, atypical antipsychotics work through this receptor complex (5-HT2AR/ mGlu2R) and signal quite differently through the complex compared to how they signal through one or the other receptor alone.^[3] The signaling through the receptor complex could predict whether a drug would act as an antipsychotic or a pro-psychotic (e.g. the hallucinogen drug LSD).^[4]

This work has opened the possibility of utilizing signaling to screen for new drugs that will target this receptor complex specifically and not cross react with dopamine receptors, which can give rise to unwanted side effects. The study also discovered that combinations of drugs simultaneously targeting each of the two receptors in the complex could be effective in animal models in cases when drugs targeting one or the other receptor alone were ineffective.^[5]

Team Structure

Six project members from three universities across the US have come together as the STAD-Schizophrenia team. The project is led by Prof. Diomedes Logothetis, the Chair of Physiology and Biophysics department at VCU School of Medicine.

Project Aims

The first project will launch when the first $250,000 has been raised.

Year 1 Milestones

• Using the signaling metric presented by Fribourg et al. (2011) for cell-based high throughput screening of:
  • new antipsychotic drugs targeting the 5-HT2A/mGluR2 receptor complex.
  • combinations of existing antipsychotic ligands targeting the 5-HT2A/mGluR2 receptor complex.
• Produce computational models of the 5-HT2AR/mGlu2R heteromeric complex and test for conformational coupling of known antipsychotic ligands and their combinations targeting this complex.
• Determine active moieties of known atypical antipsychotics to avoid interference when designing linkers to mGluR2 agonists for synthesis of bivalent ligands.
• Design in silico bivalent ligands that recognize specifically the 5-HT2A/mGlu2R receptor complex but not one or the other receptor alone.

Year 2 Milestones

• Using bivalent ligands for diagnostic purposes in PET-CT studies to monitor the level of the receptor complex in the brains of transgenic “psychotic” animals.
• Testing newly synthesized drugs in functional and binding experiments.
• Using the newly discovered ligands or combinations of existing drugs in behavioral experiments in mice to establish putative antipsychotic effectiveness.
• Initiating clinical trials, using combinations of existing drugs with promising effects on animal models, with patients resistant to treatment of single antipsychotic medications.

References

1. González-Maeso, J; Ang, RL; Yuen, T; et al. (March 2008). "Identification of a serotonin/glutamate receptor complex implicated in psychosis". Nature. 452: 93–7. doi:10.1038/nature06612. PMC 2743172. PMID 18297054.
2. Fribourg, M; Moreno, JL; Holloway, T; Provasi, D; Baki, L; Mahajan, R; Park, G; Adney, SK; Hatcher, C; Eltit, JM; Ruta, JD; Albizu, L; Li, Z; Umali, A; Shim, J; Fabiato, A; MacKerell, AD; Brezina, V; Sealfon, SC; Filizola, M; González-Maeso, J; Logothetis, DE (2011). "Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs". Cell. 147: 1011–23. doi:10.1016/j.cell.2011.09.055. PMC 3255795. PMID 22118459.
3. Fribourg, M; Moreno, JL; Holloway, T; Provasi, D; Baki, L; Mahajan, R; Park, G; Adney, SK; Hatcher, C; Eltit, JM; Ruta, JD; Albizu, L; Li, Z; Umali, A; Shim, J; Fabiato, A; MacKerell, AD; Brezina, V; Sealfon, SC; Filizola, M; González-Maeso, J; Logothetis, DE (2011). "Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs". Cell. 147: 1011–23. doi:10.1016/j.cell.2011.09.055. PMC 3255795. PMID 22118459.
4. Fribourg, M; Moreno, JL; Holloway, T; Provasi, D; Baki, L; Mahajan, R; Park, G; Adney, SK; Hatcher, C; Eltit, JM; Ruta, JD; Albizu, L; Li, Z; Umali, A; Shim, J; Fabiato, A; MacKerell, AD; Brezina, V; Sealfon, SC; Filizola, M; González-Maeso, J; Logothetis, DE (2011). "Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs". Cell. 147: 1011–23. doi:10.1016/j.cell.2011.09.055. PMC 3255795. PMID 22118459.
5. Fribourg, M; Moreno, JL; Holloway, T; Provasi, D; Baki, L; Mahajan, R; Park, G; Adney, SK; Hatcher, C; Eltit, JM; Ruta, JD; Albizu, L; Li, Z; Umali, A; Shim, J; Fabiato, A; MacKerell, AD; Brezina, V; Sealfon, SC; Filizola, M; González-Maeso, J; Logothetis, DE (2011). "Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs". Cell. 147: 1011–23. doi:10.1016/j.cell.2011.09.055. PMC 3255795. PMID 22118459.