Year 1 & 2

The Sanford-Burnham Medical Research Institute (SBMRI) Stem Cell Research Center (SCRC) supports research that (a) involves a range of pluripotent & somatic stem & progenitor cell types; (b) examines the behavior & therapeutic use of exogenous & endogenous stem/progenitor cells in animal models of a range of diseases & organ systems with an eye towards clinical translation; (c) leverages the unique strengths & resources of SBMRI, for example, in (i) chemical genomics & high-throughput screening (HTS) (for which stem cells can serve as models of diseases or biosensors for the onset of various biological processes); (ii) genomic, epigenomic, proteomic, microRNA, & metabolomic profiling; & (iii) bioinformatics. In addition, SCRC has emerged as an epicenter for education, data exchange, & collaborations in San Diego. SCRC is organized into 6 integrated sub-cores, each with its own goals & research tasks which nevertheless are interdependent & complementary, reflecting the increasingly diverse & multidisciplinary nature of the stem cell field.
•Sub-Core 1: Human Stem Cell Culture & Derivation: This Sub-Core’s goal is to provide adequate amounts of high-quality pathogen-free human embryonic stem cells (hESCs) for the routine use of SBMRI investigators as well as to generate innovative protocols for their improved derivation, maintenance, storage, differentiation, & application. This core has developed unique strategies for turning hESCs & human induced pluripotent stem cells (hIPSCs) into pure neurons that can model disease states that are then compatible with drug discovery instrumentation. The Sub-Core is also tasked with generating sufficient numbers of cells for pre-clinical translational studies that could lead to IND filings with the FDA.
•Sub-Core 2: Human Stem Cell Characterization. In addition to such routine procedures as teratoma formation & embryoid body analysis to affirm pluripotence, & the initiation of an in-house karyotyping service, characterization via this Sub-Core also, importantly, includes the use of gene and protein expression profiling. Novel insights into potential drug targets have been gleaned in this manner. In collaboration with the Proteomics Core, this Sub-Core has amassed the largest, most comprehensive comparative proteomic dataset to date of any biological system, comparing undifferentiated hESCs with their pure neurectodermal derivatives.
•Sub-Core 3. High-Throughput Analysis: This Sub-Core’s goal is to provide a bank of hESC & hIPSC lines that either bear disease-relevant assayable phenotypes or carry reporter genes that will enable high-throughput (HT) technologies for performing screens of chemical & gene libraries. Such capabilities enable users to identify molecules that (a) encourage hESCs to maintain, or hIPSCs to acquire, their pluripotent state; (b) to differentiate toward desired lineages, or (c) to block or reverse the appearance of an informative disease marker or process. The Viral Vector Core is now housed in SCRC given that the genetic modification of stem/progenitor cells has become its largest demand. This sub-core has generated a collection of reporter stem cell lines, in which a reporter gene is transcribed from various developmental stage- &/or tissue-specific promoters, making them “biosensors”. Stem cells have also been used in this manner not only to discover new candidate drugs but also to screen for drug toxicities.
•Sub-Core 4. Human Stem Cell Data Sharing & Training: One goal of this Sub-Core is to facilitate data management, analysis, & recovery. A web-accessible relational database is being upgraded to serve as a repository for complex datasets derived from experiments using gene microarray, differential proteomic profiling, & chemical library screens. Another goal is to train scientists & the lay community in the technical, ethical, & logistical issues regarding research involving embryos, stem cells, & regenerative medicine.
•Sub-Core 5. Advanced & Automated Cell Imaging: Although this sub-core consolidates the SCRC’s routine microscopic functions, it is largely built around the unique sophisticated high-resolution high-content intra- & inter-cellular imaging & HT microscopy developed at SBMRI. It can monitor phenotypes that require sophisticated, quantitative, functional, real-time, long-term readouts of subcellular locations, morphology, & physiology in living cells. We have determined that this instrumentation can be applied to hESCS & HIPSCs for HT drug discovery.
•Sub-Core 6: Human Induced Stem Cell Generation: This recently-established Sub-Core has been creating disease-modeling hIPSC lines through the reprogramming of fibroblasts from patients with a range of diseases. To date, >50 such lines have been created modeling a wide range of diseases. Such “disease-in-a-dish” technology will be used to identify mechanisms of disease, novel drug targets, & the therapeutic drugs themselves.