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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：
10677553
负责人：
Rockland Luke Wiseman
金额：
$ 51.91万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677553
关键词：
ATF6 gene Ablation Address Amyloid Amyloid Fibrils Amyloidosis Antioxidants Attenuated Autologous Stem Cell Transplantation Award Cardiac Cardiac Myocytes Cell secretion Cells Cessation of life Clonal Expansion Complex Deposition Development Disease Endoplasmic Reticulum Epithelial Cells Funding Gene Expression Profile Genes Goals Heart In Vitro Injury Kidney Light Light-Chain Immunoglobulins Modeling Molecular Monitor Organ Oxidative Stress Pathogenesis Patients Peripheral Peripheral Resistance Phototherapy Plasma Cells Population Primary Cell Cultures Proteins Regulation Serum Stress Testing Therapeutic Tissues Toxic effect amyloid pathology analog arm chemotherapy heart cell improved in vivo kidney cell mouse model next generation patient population pharmacologic primary amyloidosis of light chain type proteostasis renal epithelium response small molecule transcription factor translational potential

项目摘要

Light chain amyloidosis (AL) is a devastating disease caused by the clonal expansion of a plasma cell that secretes a destabilized, amyloidogenic immunoglobulin light chain (LC). In the serum, these LCs aggregate into toxic oligomers and amyloid fibrils that deposit in peripheral target tissues such as the kidneys and heart causing organ malfunction and eventual death. Current AL treatments use chemotherapy and autologous stem cell transplantation to ablate the underlying diseased plasma cell population, reducing AL amyloid pathology by removing the cells secreting the destabilized, aggregation-prone LC. While this strategy is effective for 70% of AL patients, the remaining 30% of patients are too sick from LC toxicity on the heart or kidney to tolerate chemotherapy. This necessitates the development of new strategies to decrease AL amyloid pathology and allow chemotherapeutic access to the diseased plasma cells in this patient population. In the previous funding period of this award, we showed that activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has significant potential to reduce AL-relevant LC toxicity through two distinct mechanisms. We found that stress-independent ATF6 activation selectively reduces the secretion and toxic aggregation of destabilized, amyloidogenic LCs. Furthermore, ATF6 activation in AL-relevant target tissues including the kidney and heart induces expression of anti-oxidant genes that protect these tissues from diverse types of oxidative stress – the same mechanism by which LCs induce toxicity in these tissues. These results suggested the possibility that activating ATF6 using small molecules could mitigate AL amyloid pathology through two complementary, tissue-specific mechanisms: 1) reducing the secretion and subsequent toxic aggregation of amyloidogenic LCs in AL plasma cells and 2) increasing resistance of peripheral target tissues to LC-associated oxidative stress. To address this potential, we are using first-in-class compounds established during the previous funding period that selectively and robustly activate ATF6. Here, we test the hypothesis that our ATF6 activating compounds can mitigate AL amyloid pathology through two distinct, tissue-specific mechanisms. We are using these compounds to define their potential to mitigate LC-associated toxicity through complementary, multi-tissue mechanisms in both plasma cells and peripheral target tissues such as the kidney and heart. We will show that our ATF6 activators induce ER proteostasis remodeling in AL patient plasma cells to selectively reduce the secretion and toxic aggregation of amyloidogenic LCs. Furthermore, we will show that pharmacologic ATF6 activation in primary heart or kidney cells attenuates LC-associated toxicity through increased expression of anti-oxidant genes. Through these efforts, we will show that our ATF6 activators offer significant translational potential to reduce AL amyloid pathology through distinct, multi-tissue mechanisms and allow chemotherapeutic access to the underlying AL-associated plasma cells in the currently untreatable population of AL patients suffering from severe kidney or cardiac involvement.

轻链淀粉样变性（AL）是由浆细胞的克隆扩增引起的破坏性疾病，分泌不稳定的淀粉样蛋白生成免疫球蛋白轻链（LC）。在血清中，这些LC聚集转化为毒性低聚物和淀粉样纤维，其存款在外周靶组织如肾脏和心脏中导致器官功能障碍最终死亡目前的AL治疗使用化疗和自体干细胞细胞移植以消融潜在的患病浆细胞群，通过以下方式减少AL淀粉样病变：除去分泌不稳定的、易于聚集的LC的细胞。虽然这一策略对70%的人有效， AL患者，其余30%的患者因LC对心脏或肾脏的毒性而病情严重，无法耐受化疗这就需要开发新的策略来减少AL淀粉样蛋白病理学，允许化疗药物进入该患者群体中的患病浆细胞。在此前的融资中，在此期间，我们发现，未折叠蛋白反应（UPR）相关的激活转录因子ATF 6通过两种不同的途径降低AL相关的LC毒性，机制等我们发现，应激非依赖性ATF 6激活选择性地减少了分泌和毒性。不稳定的淀粉样蛋白生成LC的聚集。此外，AL相关靶组织中的ATF 6活化包括肾脏和心脏诱导抗氧化基因的表达，氧化应激类型-LC在这些组织中诱导毒性的相同机制。这些结果提示使用小分子激活ATF 6可以减轻AL淀粉样病变的可能性通过两种互补的组织特异性机制：1）减少分泌和随后的毒性 AL浆细胞中淀粉样蛋白生成LC的聚集和2）外周靶组织的抵抗力增加 LC相关的氧化应激。为了解决这一潜力，我们正在使用一流的化合物，在上一个供资期间，有选择地和有力地激活ATF 6。在这里，我们检验这个假设我们的ATF 6激活化合物可以通过两种不同的组织特异性的，机制等我们正在使用这些化合物来确定它们减轻LC相关毒性的潜力通过浆细胞和外周靶组织中的互补的多组织机制，肾脏和心脏我们将证明我们的ATF 6激活剂在AL患者中诱导ER蛋白稳态重构，浆细胞选择性地减少淀粉样蛋白生成LC的分泌和毒性聚集。而且我们将显示在原代心脏或肾脏细胞中的药理学ATF 6活化减弱LC相关毒性通过增加抗氧化基因的表达。通过这些努力，我们将证明我们的ATF 6 激活剂提供了显著的翻译潜力，通过不同的，多组织，机制，并允许化疗药物进入目前的基础AL相关浆细胞，患有严重肾脏或心脏受累的不可治疗的AL患者群体。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.

DOI：
10.1021/acschembio.1c00810
发表时间：
2021-12-17
期刊：
ACS chemical biology
影响因子：
4
作者：
Rosarda JD;Baron KR;Nutsch K;Kline GM;Stanton C;Kelly JW;Bollong MJ;Wiseman RL
通讯作者：
Wiseman RL

Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease.

DOI：
10.1042/bcj20190312
发表时间：
2020-05-15
期刊：
The Biochemical journal
影响因子：
0
作者：
Romine, Isabelle C;Wiseman, R Luke
通讯作者：
Wiseman, R Luke

Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer.

DOI：
10.1126/sciadv.abo1123
发表时间：
2022-09-30
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.

KEAP1 传感器赖氨酸的琥珀酰化可促进 NRF2 激活。

DOI：
10.1101/2023.05.08.539908
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Ibrahim,Lara;Stanton,Caroline;Nutsch,Kayla;Nguyen,Thu;Li-Ma,Chloris;Ko,Yeonjin;Lander,GabrielC;Wiseman,RLuke;Bollong,MichaelJ
通讯作者：
Bollong,MichaelJ

Characterization of an A-Site Selective Protein Disulfide Isomerase A1 Inhibitor.

DOI：
10.1021/acs.biochem.8b00178
发表时间：
2018-04-03
期刊：
Biochemistry
影响因子：
2.9
作者：
Cole KS;Grandjean JMD;Chen K;Witt CH;O'Day J;Shoulders MD;Wiseman RL;Weerapana E
通讯作者：
Weerapana E