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（由申请方提供）：轻链淀粉样变性（AL）是一种由恶性浆细胞克隆性扩增引起的破坏性疾病，该浆细胞分泌不稳定的淀粉样蛋白免疫球蛋白轻链（LC）。 淀粉样蛋白生成LC经历错误折叠和浓度依赖性聚集成毒性寡聚体和淀粉样蛋白原纤维，其存款在远端组织如心脏上。 因此，AL患者患有浆细胞恶性肿瘤和系统性淀粉样蛋白疾病。 目前的AL治疗使用化疗和自体干细胞置换来减少克隆浆细胞群，仅间接影响AL淀粉样蛋白病理学。 虽然这种方法对70%的患者有效，但其余30%的患者因LC蛋白毒性而无法耐受这种治疗。 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。 开发这种策略的挑战是AL相关的淀粉样蛋白生成LC序列的异质性。 因此，任何改善AL淀粉样病变的策略都必须针对介导异质性淀粉样LC毒性的基本生物学机制，但不会全面损害生物体免疫或内源性分泌蛋白质组的分泌。 我们假设内质网（ER）蛋白质稳态途径的活性是毒性LC聚集的关键决定因素，可以靶向改善AL淀粉样病变。 ER蛋白质稳态途径可以促进不稳定的淀粉样蛋白的分泌，增加其血清浓度，可用于毒性错误折叠和聚集。 因此，调节ER蛋白酶抑制途径的活性提供了一个独特的机会，以降低血清浓度的不稳定，淀粉样蛋白生成LC，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（UPR）相关转录因子的应激非依赖性激活，适应ER蛋白抑制途径减少了不稳定的淀粉样蛋白生成LC的分泌和细胞外聚集，而不影响非淀粉样蛋白生成LC，IgG或全球内源性分泌蛋白质组的分泌。 在这里，我们定义的贡献ER蛋白酶抑制途径在毒性LC聚集通过识别途径优先参与分泌，细胞外聚集和随后的毒性淀粉样变LC。 此外，我们将证明，小分子ER蛋白酶抑制调节剂，改变这些ER蛋白酶抑制途径的活性，减少分泌和毒性聚集的不稳定，淀粉样蛋白生成LC在AL患者源性浆细胞。 通过这些努力，我们将表明ER蛋白抑制通路的活性是决定AL淀粉样病变的基本决定因素。 此外，我们将确定一流的小分子ER蛋白质稳态调节剂，靶向这些途径，以减弱淀粉样蛋白生成LC的分泌和毒性聚集。 我们的研究结果将确定ER蛋白质稳态调节作为改善AL淀粉样蛋白病理的第一策略，然后可以与化疗药物联合使用，以治疗患有严重LC蛋白毒性的AL患者队列。