Exploring the Chemistry and Biology of Arm-Selective UPR Activation

描述(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正常细胞功能和活力至关重要。内质网蛋白抑制网络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、癌症和心脏疾病。为了保护内质网中和整个分泌途径中的蛋白质动态平衡，细胞进化出三个机械上不同的信号臂来调节内质网蛋白稳态，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内质网应激的全球反应，但最近的证据表明，对UPR特定臂的选择性调节可能在正常发育中发挥作用，并被操纵以治疗蛋白质错误折叠疾病。我们的目标是通过研究UPR的特定手臂对特定应激源(例如蛋白质错误折叠负担的类型和大小)的相对贡献，以及这种选择性如何作为细胞和组织类型的函数(特定目标1)来揭示手臂选择性UPR激活的化学和生物学。此外，我们正在开发针对手臂特异性UPR激活的记者，这些记者正被应用于发现UPR的小分子手臂特异性激活剂或抑制剂(特定目标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发展。

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.