Exploring the Chemistry and Biology of Arm-Selective UPR Activation

探索臂选择性 UPR 激活的化学和生物学

• 批准号: 8713895
• 负责人: Christina Barnes Cooley
• 金额: $ 4.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-16 至 2015-07-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713895
• 关键词: Address; Aging; Biological Assay; Biology; Cardiac; Cell Line; Cell Survival; Cell physiology; Cells; Chemistry; Development; Diabetes Mellitus; Disease; Disease model; Dominant-Negative Mutation; Down-Regulation; Endoplasmic Reticulum; Equilibrium; Evaluation; Exposure to; Firefly Luciferases; Gene Expression Profile; Goals; Heat-Shock Response; Histocompatibility Testing; Homeostasis; Inherited; Integral Membrane Protein; Lead; Learning; Libraries; Link; Liver; Lysosomal Storage Diseases; Maintenance; Malignant Neoplasms; Mammalian Cell; Metabolic Diseases; Mutation; Neurodegenerative Disorders; Neurons; Normal Cell; Nuclear; Organism; Outcome; Pathway interactions; Patients; Play; Process; Protein Biosynthesis; Proteins; Proteome; Pulmonary Emphysema; RNA Interference; RNA Splicing; Relative (related person); Renilla Luciferases; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Trypsin; arm; base; cell type; endoplasmic reticulum stress; human disease; inhibitor/antagonist; novel; promoter; protein aggregation; protein misfolding; response; small molecule; stressor; therapy development; trafficking; transcription factor

DESCRIPTION (provided by applicant): The ability of cells and organisms to regulate protein homeostasis, or the balance of protein synthesis, assembly, folding, aggregation and secretion in the endoplasmic reticulum (ER) is critical to normal cell function and viability. Deficiencies i the ER proteostatic network are implicated in aging and many types of human disease including metabolic and neurodegenerative disorders, cancer and cardiac maladies. In order to protect protein homeostasis in the ER and throughout the secretory pathway, cells have evolved three mechanistically distinct signaling arms that regulate ER proteostasis, collectively referred to as the unfolded protein response (UPR). While the three arms of the UPR were originally considered to be a global response to ER stress, recent evidence suggests that selective modulation of specific arms of the UPR could play a role in normal development and be manipulated to treat protein misfolding diseases. Our objective is to unravel the chemistry and biology of arm-selective UPR activation by examining the relative contributions of specific arms of the UPR in response to particular stressors, such as the type and magnitude of the protein misfolding burden, and how that selectivity changes as a function of cell and tissue type (Specific Aim 1). Moreover, we are developing reporters for arm-specific UPR activation, which are being applied to discover small molecule arm-specific activators or inhibitors of the UPR (Specific Aim 2). The discovery of arm-selective UPR modulators could lead to the development of therapeutic agents for the treatment of protein misfolding diseases.

描述（由申请人提供）：细胞和生物体调节蛋白质稳态的能力，或内质网（ER）中蛋白质合成、组装、折叠、聚集和分泌的平衡对于正常细胞功能和活力至关重要。内质网蛋白抑制网络的缺陷与衰老和许多类型的人类疾病有关，包括代谢和神经退行性疾病、癌症和心脏病。为了保护内质网和整个分泌途径中的蛋白质稳态，细胞进化出了三个机制不同的信号臂来调节内质网蛋白质稳态，统称为未折叠蛋白反应（UPR）。虽然 UPR 的三个臂最初被认为是对 ER 应激的整体反应，但最近的证据表明，UPR 特定臂的选择性调节可以在正常发育中发挥作用，并可用于治疗蛋白质错误折叠疾病。我们的目标是通过检查 UPR 特定臂对特定应激源的相对贡献（例如蛋白质错误折叠负担的类型和程度，以及选择性如何随着细胞和组织类型的函数而变化）来阐明臂选择性 UPR 激活的化学和生物学（具体目标 1）。此外，我们正在开发针对手臂特异性 UPR 激活的报告基因，该报告基因可用于发现小分子手臂特异性 UPR 激活剂或抑制剂（具体目标 2）。臂选择性 UPR 调节剂的发现可能会导致治疗蛋白质错误折叠疾病的治疗药物的开发。