Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis

制定改善轻链淀粉样变性淀粉样蛋白病理学的策略

• 批准号: 9104759
• 负责人: Rockland Luke Wiseman
• 金额: $ 43.31万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104759
• 关键词: Affect; Amyloid Fibrils; Amyloidosis; Attenuated; Autologous; Biochemical Genetics; Biological Assay; Cancerous; Cell secretion; Cells; Clonal Expansion; Critical Pathways; Deposition; Development; Disease; Distal; Endoplasmic Reticulum; Goals; Heart; Heterogeneity; Immunity; Light; Light-Chain Immunoglobulins; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Pathology; Pathway interactions; Patients; Plasma Cells; Population; Protein Overexpression; Proteins; Proteome; Publishing; RNA Interference; Regulation; Serum; Signal Pathway; Stem cells; Stress; Tissues; Toxic effect; amyloid pathology; chemotherapy; cohort; defined contribution; extracellular; genetic approach; high throughput screening; meetings; novel therapeutics; patient population; primary amyloidosis of light chain type; public health relevance; research study; response; small molecule; transcription factor

 DESCRIPTION (provided by applicant): Light chain amyloidosis (AL) is a devastating disease caused by the clonal expansion of a malignant plasma cell that secretes a destabilized, amyloidogenic immunoglobulin light chain (LC). Amyloidogenic LCs undergo misfolding and concentration-dependent aggregation into toxic oligomers and amyloid fibrils that deposit on distal tissues such as the heart. Thus, AL patients suffer from both a plasma cell malignancy and a systemic amyloid disease. Current AL treatments use chemotherapy and autologous stem cell replacement to decrease the clonal plasma cell population, only indirectly affecting AL amyloid pathology. While this approach is efficient for 70% of patients, the remaining 30% of patients are too sick from LC proteotoxicity to tolerate this treatment. In order to treat these patients, new therapies must be developed to treat the LC proteotoxicity in AL pathology. A challenge in developing such strategies is the heterogeneity of AL-associated, amyloidogenic LC sequences. Thus, any strategy to ameliorate AL amyloid pathology must target a fundamental biologic mechanism that mediates toxicity of heterogeneous amyloidogenic LCs, but does not globally compromise organismal immunity or secretion of the endogenous secreted proteome. We hypothesize that the activity of endoplasmic reticulum (ER) proteostasis pathways is a critical determinant in toxic LC aggregation that can be targeted to ameliorate AL amyloid pathology. ER proteostasis pathways can facilitate secretion of destabilized, amyloidogenic proteins, increasing their serum concentrations available for toxic misfolding and aggregation. Thus, modulating the activity of ER proteostasis pathways offers a unique opportunity to reduce serum concentrations of destabilized, amyloidogenic LCs and thus decrease proteotoxic LC aggregation. We show that adapting ER proteostasis pathways through stress-independent activation of select Unfolded Protein Response (UPR)-associated transcription factors reduces the secretion and extracellular aggregation of a destabilized, amyloidogenic LC, without affecting secretion of a non-amyloidogenic LC, IgGs or the global endogenous secreted proteome. Here, we define the contribution of ER proteostasis pathways in toxic LC aggregation by identifying pathways preferentially involved in the secretion, extracellular aggregation and subsequent toxicity of amyloidogenic LCs. Furthermore, we will demonstrate that small molecule ER proteostasis regulators that alter the activity of these ER proteostasis pathways reduce secretion and toxic aggregation of destabilized, amyloidogenic LCs in AL patient-derived plasma cells. Through these efforts, we will show that the activity of ER proteostasis pathways is a fundamental determinant in dictating AL amyloid pathology. Furthermore, we will identify first-in-class small molecule ER proteostasis regulators that target these pathways to attenuate secretion and toxic aggregation of amyloidogenic LCs. Our results will establish ER proteostasis regulation as the first strategy to ameliorate AL amyloid pathology that can then be used in combination with chemotherapeutics to treat the AL patient cohort suffering from severe LC proteotoxicity.

 描述（由申请人提供）：轻链淀粉样变性（AL）是一种毁灭性的疾病，由恶性浆细胞的克隆扩张引起，该恶性浆细胞分泌不稳定的淀粉样变性免疫球蛋白轻链（LC），发生错误折叠和浓度依赖性聚集成淀粉样变性。有毒寡聚体和淀粉样原纤维沉积在心脏等远端组织上，因此，AL 患者同时患有浆细胞恶性肿瘤和浆细胞恶性肿瘤。目前的 AL 治疗使用化疗和自体干细胞替代来减少克隆浆细胞群，只能间接影响 AL 淀粉样蛋白病理，虽然这种方法对 70% 的患者有效，但其余 30% 的患者病情严重。为了治疗这些患者，必须开发新的疗法来治疗 AL 病理学中的 LC 蛋白毒性，开发此类策略的一个挑战是 AL 相关的异质性。因此，任何改善 AL 淀粉样蛋白病理学的策略都必须针对介导异质性淀粉样蛋白形成 LC 的基本毒性机制，但不会全面损害机体免疫或内源性分泌蛋白质组的分泌。 ER) 蛋白质稳态途径是有毒 LC 聚集的关键决定因素，可用于改善 AL 淀粉样蛋白病理学。蛋白质稳态途径可以促进不稳定的淀粉样蛋白的分泌，增加其可用于毒性错误折叠和聚集的血清浓度，因此，调节 ER 蛋白质稳态途径的活性提供了一个独特的机会来降低不稳定的淀粉样蛋白 LC 的血清浓度，从而减少蛋白毒性 LC 聚集。我们表明，通过选择未折叠蛋白反应的应激独立激活来适应内质网蛋白稳态途径。 (UPR) 相关转录因子减少不稳定的淀粉样变性 LC 的分泌和细胞外聚集，而不影响非淀粉样变性 LC、IgG 或整体内源性分泌蛋白质组的分泌。在此，我们定义了 ER 蛋白稳态途径在毒性中的贡献。通过识别优先参与淀粉样变性 LC 的分泌、细胞外聚集和随后的毒性的途径来进行 LC 聚集。将证明改变这些 ER 蛋白质稳态途径活性的小分子 ER 蛋白质稳态调节剂可减少 AL 患者来源的浆细胞中不稳定的淀粉样蛋白形成 LC 的分泌和毒性聚集。通过这些努力，我们将证明 ER 蛋白质稳态途径的活性是此外，我们将确定针对这些的一流小分子 ER 蛋白质稳态调节剂。我们的研究结果将确立 ER 蛋白稳态调节作为改善 AL 淀粉样蛋白病理的第一个策略，然后可与化疗药物联合使用来治疗患有严重 LC 蛋白毒性的 AL 患者群体。