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: 8456918
• 负责人: Christina Barnes Cooley
• 金额: $ 4.92万
• 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 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456918
• 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. PUBLIC HEALTH RELEVANCE: The ability to selectively activate or inhibit specific arms of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) is desirable in order to develop therapies for the treatment of numerous protein misfolding disorders, such as neurodegenerative disease, metabolic disorders and cancer. We are developing sensitive reporters for arm-selective activation of the UPR to learn how each specific arm of the UPR in various cells and tissues contributes to protection from disease- associated protein misfolding stressors and to discover small molecule arm-specific UPR modulators. Elucidating the specific activation profiles relevant to particular disease states and discovering molecules which can selectively modulate particular arms of the UPR could lead to the development of small molecule therapeutics for the treatment of protein misfolding diseases, for example lysosomal storage disease or ¿-1 anti-trypsin associated emphysema.

描述（由申请人提供）：细胞和生物体调节蛋白质稳态或内质网（ER）中蛋白质合成、组装、折叠、聚集和分泌平衡的能力对正常细胞功能和活力至关重要。内质网蛋白抑制网络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ER和整个分泌途径中的蛋白质稳态，细胞已经进化出三种机制上不同的信号传导臂，其调节ER蛋白稳态，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应激的全球反应，但最近的证据表明，选择性调节UPR的特定臂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，如蛋白质错误折叠负担的类型和幅度，以及选择性如何随细胞和组织类型而变化，来揭示臂选择性UPR激活的化学和生物学（具体目标1）。此外，我们正在开发用于臂特异性UPR激活的报告基因，这些报告基因正被应用于发现小分子臂特异性UPR激活剂或抑制剂（特异性目标2）。臂选择性UPR调节剂的发现可能导致用于治疗蛋白质错误折叠疾病的治疗剂的开发。 公共卫生相关性：选择性激活或抑制内质网（ER）中未折叠蛋白质应答（UPR）的特定臂的能力是期望的，以便开发用于治疗许多蛋白质错误折叠病症（例如神经变性疾病、代谢病症和癌症）的疗法。我们正在开发用于臂选择性激活UPR的敏感报告分子，以了解各种细胞和组织中UPR的每个特定臂如何有助于保护免受疾病相关蛋白质错误折叠应激源的影响，并发现小分子臂特异性UPR调节剂。阐明与特定疾病状态相关的特异性活化谱和发现可以选择性调节UPR的特定臂的分子可以导致用于治疗蛋白质错误折叠疾病（例如溶酶体贮积病或抗胰蛋白酶相关的肺气肿）的小分子治疗剂的开发。