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) 是一种毁灭性的疾病，由浆细胞的克隆扩张引起，分泌不稳定的淀粉样蛋白免疫球蛋白轻链 (LC)，这些 LC 在血清中聚集。转化为有毒低聚物和淀粉样原纤维，沉积在肾脏和心脏等外周靶组织中导致器官功能障碍并最终导致死亡。目前的 AL 治疗采用化疗和自体干细胞。细胞移植消除潜在的患病浆细胞群，通过以下方式减少 AL 淀粉样蛋白病理：去除分泌不稳定、易于聚集的 LC 的细胞，而这种策略对 70% 的细胞有效。 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而无法耐受这需要开发新的策略来减少 AL 淀粉样蛋白病理学和在之前的资助中，允许化疗药物接触到该患者群体中的患病浆细胞。在此奖项期间，我们发现与未折叠蛋白反应（UPR）相关的激活转录因子 ATF6 通过两种不同的方式具有降低 AL 相关 LC 毒性的巨大潜力我们发现应激无关的 ATF6 激活选择性地减少分泌和毒性。不稳定的淀粉样变性 LC 的聚集此外，AL 相关靶组织中 ATF6 的激活。包括肾脏和心脏在内，诱导抗氧化基因的表达，保护这些组织免受多种因素的影响氧化应激的类型——与 LC 在这些组织中诱导毒性的机制相同。表明使用小分子激活 ATF6 可以减轻 AL 淀粉样蛋白病理学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 浆细胞中淀粉样变性 LC 的聚集以及 2) 外周靶组织的抵抗力增加为了解决这一潜力，我们正在使用已建立的一流化合物。在此，我们测试了该假设。我们的 ATF6 激活化合物可以通过两种不同的、组织特异性的方式减轻 AL 淀粉样蛋白病理学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性多组织机制，例如我们将证明我们的 ATF6 激活剂可诱导 AL 患者的 ER 蛋白质稳态重塑。浆细胞选择性地减少淀粉样变性LC的分泌和毒性聚集。将表明原代心脏或肾细胞中 ATF6 的药理学激活可减弱 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 ATF6。激活剂具有显着的转化潜力，可通过不同的多组织减少 AL 淀粉样蛋白病理学机制并允许化疗药物进入当前 AL 相关的潜在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）

Proteostasis and Beyond: ATF6 in Ischemic Disease.

蛋白质稳态及其他：ATF6 在缺血性疾病中的作用。

DOI：
10.1016/j.molmed.2019.03.005
发表时间：
2019-06-01
期刊：
Trends in molecular medicine
影响因子：
13.6
作者：
C. Glembotski;Jessica D. Rosarda;R. L. Wiseman
通讯作者：
R. L. Wiseman

Covalent targeting as a common mechanism for inhibiting NLRP3 inflammasome assembly.

共价靶向作为抑制 NLRP3 炎性体组装的常见机制。

DOI：
发表时间：
2023-06-01
期刊：
影响因子：
0
作者：
Stanton, Caroline;Sun, Jie;Nutsch, Kayla;Rosarda, Jessica D;Nguyen, Thu;Li;Kutseikin, Sergei;Saez, Enrique;Teijaro, John R;Wiseman, R Luke;Bollong, Michael J
通讯作者：
Bollong, Michael J

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

代谢激活的蛋白质稳态调节剂通过激活 NRF2 来防止谷氨酸毒性。

DOI：
发表时间：
2021-12-17
期刊：
影响因子：
4
作者：
Rosarda, Jessica D;Baron, Kelsey R;Nutsch, Kayla;Kline, Gabriel M;Stanton, Caroline;Kelly, Jeffery W;Bollong, Michael J;Wiseman, R Luke
通讯作者：
Wiseman, R Luke

Regulation of Human b-Glucuronidase by A 23187 and Thapsigargin in the Hepatoma Cell Line HepG 2

A 23187 和 Thapsigargin 在肝癌细胞系 HepG 2 中对人 b-葡萄糖醛酸酶的调节