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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：轻链淀粉样变性（AL）是一种由恶性血浆细胞的克隆扩张引起的毁灭性疾病，该疾病会促成不稳定的，淀粉样蛋白生成的免疫球蛋白光链（LC）。淀粉样蛋白生成的LC会经历错误折叠和浓度依赖性聚集到有毒的寡聚物和淀粉样蛋白原纤维中，这些淀粉样蛋白会沉积在远端组织（如心脏）上。 AL患者患有浆细胞恶性肿瘤和全身性淀粉样蛋白疾病。当前的AL治疗使用化学疗法和自体干细胞置换来减少克隆血浆细胞群，仅间接影响AL淀粉样蛋白病理。尽管这种方法对于70％的患者有效，但剩下的30％的患者因LC蛋白毒性而生病，无法忍受这种疗法。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。制定此类策略的挑战是AL相关的淀粉样蛋白生成LC序列的异质性。因此，任何改善淀粉样蛋白病理学的策略都必须针对介导异质淀粉样蛋白生成LCS毒性的基本生物学机制，但并不能在全球范围内妥协有机免疫或内源性分泌蛋白质组的分泌。我们假设内质网（ER）蛋白质途径的活性是有毒LC聚集的关键决定因素，可以针对改善AL淀粉样蛋白病理学。 ER蛋白质途径可以促进分泌不稳定的淀粉样蛋白蛋白，从而增加其血清浓度可用于有毒的错误折叠和聚集。因此，调节ER蛋白抑制途径的活性为降低血清浓度不稳定的淀粉样蛋白酶生成LCS，从而降低蛋白毒性LC聚集提供了独特的机会。我们表明，通过不依赖压力的蛋白质反应（UPR）相关的转录因子来适应ER蛋白抑制途径，从而减少了分泌的分泌和提取的细胞淀粉样蛋白生成LC的分泌，而无需影响非氨基化LC，IGGS，IGGS，IGGS或全局分泌的蛋白质分泌的分泌。在这里，我们通过更多地识别途径来定义ER蛋白抑制途径在毒性LC聚集中的贡献，我们将证明，小分子ER蛋白抑制剂改变了这些ER蛋白抗体途径的活性，从而减少了破坏稳定的疗效，溶性LCS在患者中的分泌和毒性聚集。通过这些努力，我们将证明ER蛋白质途径的活性是决定AL淀粉样蛋白病理学的基本决定剂。此外，我们将确定针对这些途径的第一类小分子ER蛋白抑制剂调节剂，以减轻淀粉样蛋白生成LC的分泌和有毒聚集。我们的结果将建立ER蛋白质的调节作为改善淀粉样蛋白病理学的第一种策略，然后可以与化学治疗剂结合使用，以治疗患有严重LC蛋白毒性的AL患者队列。