Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse

靶向 IRE-1a/XBP-1 轴控制慢性 GVHD 和白血病复发

基本信息

批准号：
10179448
负责人：
Xue-Zhong Yu
金额：
$ 7.28万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-01-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179448
关键词：
ATF6 gene Allogeneic Bone Marrow Transplantation Allogenic Antibodies Antibody Formation Antigen-Presenting Cells Apoptosis Area B Cell Proliferation B-Cell Activation B-Cell Leukemia B-Lymphocytes Binding Proteins Biology Blood Cells Cellular Stress Response Cellular biology Chronic Clinic Complication Cytotoxic T-Lymphocytes Dendritic Cells Dendritic cell activation Development Disease Endoplasmic Reticulum Growth Hematologic Neoplasms Hematopoietic Hematopoietic Stem Cell Transplantation Immune Immune response Immune system Incidence Leukemic Cell Lymphocyte Function Malignant Neoplasms Messenger RNA Molecular Morbidity - disease rate Multiple Myeloma Mus Nuclear Patients Pharmacology Play Pre-Clinical Model Prevention Prophylactic treatment Proteins Publishing RNA Splicing Recurrence Regimen Research Role Severities Severity of illness Signal Transduction T cell response T-Lymphocyte Testing Therapeutic Effect Translating Transplantation chronic graft versus host disease defined contribution design endoplasmic reticulum stress genetic approach graft vs host disease graft vs leukemia effect hematopoietic cell transplantation inhibitor/antagonist leukemia leukemia relapse leukemia/lymphoma mortality novel novel therapeutics plasma cell differentiation preservation prophylactic protein degradation protein folding response therapeutic target transcription factor

项目摘要

Abstract Hematological malignancies that include leukemia and lymphoma are often treated with allogeneic hematopoietic stem cell transplantation (allo-HCT). However, chronic graft-versus-host disease (cGVHD) remains a prominent cause of transplant-related morbidity and mortality despite available immunosuppressive regimens. Few prophylactic strategies have been successful at reducing the incidence of cGVHD in patients after allo-HCT. An area previously unexplored as a treatment for cGVHD involves the unfolded protein response (UPR). Three master regulators control the UPR: PERK, IRE-1α, and ATF6. When IRE-1α becomes activated, its primary function is to splice Xbox binding protein-1 (XBP-1u) mRNA. Spliced XBP-1 (XBP-1s) mRNA is translated into XBP-1 protein which acts as an effective nuclear transcription factor. Immune responses such as B-cell proliferation and antibody production require large amounts of properly folded proteins. As a transcription factor, XBP-1 protein relieves ER stress by up regulating cellular machinery responsible for protein folding and degradation. XBP-1 is therefore required for the effector function and survival of various types of immune cells that are susceptible to ER stress. IRE-1α/XBP-1 signaling axis plays predominate roles in B cells and dendritic cells (DCs) among other immune cells. Built upon published findings and our preliminary observations, we will evaluate how IRE-1α/XBP-1 signaling axis impacts in the development of cGVHD after allo-HCT through regulating B cells and DCs among others. Our Central Hypothesis is that XBP-1 plays an essential role for B-cell and DC activation and function, and targeting XBP-1 will restrain allogeneic responses leading to the control of cGVHD while preserving the integrity of cytotoxic T lymphocytes (CTL) and thus maintaining the graft-versus-leukemia (GVL) effect. This hypothesis will be tested in the following two Specific Aims: 1) Define the contribution of XBP-1 on hematopoietic cells in the development of cGVHD after allo-HCT using a genetic approach; 2) Determine the therapeutic effect of targeting XBP-1 in the control of cGVHD and leukemia relapse using a pharmacological approach. The current study is expected to further understand the cell biology how UPR regulates immune responses, reveal the role for IRE-1α/XBP-1 signaling axis in the development of cGVHD and relatable hematologic malignancies, and provide a novel therapy for controlling cGVHD and leukemia relapse in after allo-HCT.

抽象的包括白血病和淋巴瘤在内的血液恶性肿瘤通常采用同种异体治疗造血干细胞移植（allo-HCT）然而，慢性移植物抗宿主病（cGVHD）。尽管有可用的免疫抑制药物，但它仍然是移植相关发病率和死亡率的一个主要原因很少有预防策略能够成功降低患者 cGVHD 的发生率。 allo-HCT 之前未探索的 cGVHD 治疗领域涉及未折叠蛋白。当 IRE-1α 变为时，三个主调节器控制 UPR：PERK、IRE-1α 和 ATF6。激活后，其主要功能是剪接 Xbox 结合蛋白-1 (XBP-1u) mRNA。 mRNA 被翻译成 XBP-1 蛋白，作为有效的核转录因子。 B 细胞增殖和抗体产生等反应需要大量正确折叠的作为一种转录因子，XBP-1 蛋白通过上调细胞机制来缓解 ER 应激。因此，XBP-1 负责蛋白质折叠和降解，是效应子功能所必需的。易受 ER 应激影响的各类免疫细胞的存活。在其他免疫细胞中，B 细胞和树突状细胞 (DC) 中起主导作用基于已发表的研究结果。和我们的初步观察，我们将评估 IRE-1α/XBP-1 信号轴如何影响通过调节 B 细胞和 DC 等来控制异基因 HCT 后 cGVHD 的发生。假设 XBP-1 对于 B 细胞和 DC 的激活和功能发挥重要作用，并且靶向 XBP-1 将抑制同种异体反应，从而控制 cGVHD，同时保留细胞毒性 T 的完整性淋巴细胞（CTL），从而维持移植物抗白血病（GVL）效应，这一假设将得到检验。以下两个具体目标： 1) 定义 XBP-1 对造血细胞的贡献使用遗传方法确定异基因 HCT 后 cGVHD 的治疗效果；使用药理学方法靶向 XBP-1 控制 cGVHD 和白血病复发。研究有望进一步了解细胞生物学中UPR如何调节免疫反应，揭示其作用 IRE-1α/XBP-1 信号轴在 cGVHD 和相关血液恶性肿瘤发生过程中的作用，以及为allo-HCT后控制cGVHD和白血病复发提供了一种新疗法。