Proteogenetics

描述（由申请人提供）：本研究计划的目标是开发一种策略，利用具有明确疾病基因型的患者来源细胞，通过大规模蛋白质组学和网络分析来识别中断的分子途径。我们将这种方法命名为蛋白质遗传学。人类诱导多能干细胞（hiPSC）彻底改变了从患者身上研究人类疾病的能力。现在有可能从患有疾病的患者身上获得成纤维细胞，并将这些细胞重新编程为多能干细胞，然后将它们分化成与疾病状态相关的细胞类型。这扭转了长期以来对人类疾病研究的限制，即直接使用来自细胞的能力

DESCRIPTION (provided by applicant): The goal of this research proposal is to develop a strategy to use patient derived cells with defined disease genotypes to identify disrupted molecular pathways through large-scale proteomics and network analysis. We have named this approach proteogenetics. Human induced pluripotent stem cells (hiPSC) have revolutionized the ability to study human diseases from patients. It is now possible to obtain fibroblasts from patients suffering from a disease and to reprogram the cells to pluripotent stem cells and then differentiate them into a cell type associated with the disease state. This reverses a long standing limitation for the study of human diseases has been the ability to use cells directly from patients with the appropriate disease phenotype and genotype. To study Rett's syndrome, we will combine vertical (unaffected parent and affected child) and horizontal genetics (different mutations in families/patients) to measure proteomic changes in affected forebrain neuronal cells (FNC) derived through fibroblasts and hiPSCs. For schizophrenia, we will use cells from several patients, but will not have access to unaffected parents. We will use network analysis techniques to identify pathway based phenotypic differences from protein and phosphoprotein expression patterns. Fibroblasts have been obtained from unaffected parents and affected children for Rett's syndrome and schizophrenia patients by Professor Allyson Moutri's (UCSD) and Professor Fred Gage's laboratory (The Salk Institute), respectively. These cells have been reprogrammed to iPSCs and differentiated into forebrain neurons for proteomic analysis. Our hypothesis is that this approach will identify specific molecular processes disrupted by disease.