Exploring the Chemistry and Biology of Arm-Selective UPR Activation

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。内质网蛋白酶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，细胞进化出三种机制不同的信号臂来调节内质网的蛋白质稳态，统称为未折叠蛋白反应（UPR）。虽然普遍定期审议的三个环节最初被认为是对内质网应激的全局反应，但最近的证据表明，对普遍定期审议的特定环节的选择性调节可能在正常发育中发挥作用，并可被操纵以治疗蛋白质错误折叠疾病。我们的目标是通过检查UPR特定臂在特定应激源（如蛋白质错误折叠负荷的类型和大小）下的相对贡献，以及这种选择性如何随着细胞和组织类型的变化而变化，来揭示臂选择性UPR激活的化学和生物学（specific Aim 1）。此外，我们正在开发针对手臂特异性UPR激活的报告，用于发现小分子的手臂特异性UPR激活剂或抑制剂（Specific Aim 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剂的开发。

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.