Thanks to a $50,000 grant from the California Bipolar Foundation (CBF) to post-doctoral research fellow Dr. Illyas Singec at the Burnham Institute for Medical Research (BIMR), a research team headed by Dr. Evan Snyder (along with co-investigators Drs. Dieter Wolfe and Lawrence Brill), was able to accumulate sufficient preliminary data to win an extremely competitive Grand Opportunities (GO) grant from the National Institute of Mental Health to explore the molecular basis of Bipolar Disorder (BPD).
BPD is a severe and prominent societal malady with poorly understood etiology. This neuropsychiatric condition is defined by a lifetime of relapsing and remitting manic and depressive episodes and has been shown to have strong genetic linkage with familial predisposition.
The recently funded project represents the convergence of a series of cutting-edge technologies and approaches to better understand the molecular basis of this condition and hopefully identify better and more rational treatments.
Authentic laboratory models -- including animal models -- that reliably represent aspects of BPD (or most human neuropsychiatric diseases) have been difficult to establish. Recent advances in stem cell biology have allowed the conversion of skin cells taken from actual patients into "stem-like cells" called "human induced pluripotent stem cells (hIPSCs)". These skin cells can be "reprogrammed" to the point that they can be induced to yield almost every mature cell type of the body following various differentiation protocols, including brain cells. Such hIPSC-derived brain cells will bear the "molecular fingerprint" of the patient from which the skin cells were taken. Therefore, the first cutting-edge technique to be employed by the team will be to develop a representative, predictive model system to explore function and regulation in brain cells that faithfully recapitulate the underlying defects of actual human patients with BPD.
The team will generate hIPSCs from small samples of skin cells from a range of actual patients with BPD, turn those cells into brain cells, and then subject those cells to phosphoproteomic analysis in order to understand how the cell controls various important functions. To make the study as revealing and specific as possible, the hIPSCs from BPD patients - both responsive to lithium and non-responsive to lithium - will be compared to hIPSCs generated from unaffected patients, from patients with schizophrenia but not BPD, from patients with non-neurologic diseases, and from patients with neurogenetic disorders lacking a psychiatric component.
Importantly, this valuable dataset will be made available to the broader research community so that complementary parallel studies may be launched on the basis of these proteomic and phosphoproteomic results by other investigators in the field in order to accelerate progress in BPD and other neuropsychiatric disorders. Furthermore, the insights and databases generated by this project may be applicable to many cell types, organ systems, and other diseases.
Learning to make hIPSCs, how to turn them into brain cells at various stages of development, and performing pilot phosphoproteomic analysis on immature stem cells was aided by seed money from CBF.
The team will now be looking for volunteers from the CBF community who might donate a tiny piece of skin from which these stem-like cells can be made and can be used for the study. There is no restriction on age of donor.
California Bipolar Foundation