Proteasome targeting for alloreactive plasma cells

针对同种异体反应性浆细胞的蛋白酶体

基本信息

批准号：
10652461
负责人：
David M Allman
金额：
$ 65.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-13 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652461
关键词：
Acute Affect Alloantigen Antibodies Antibody titer measurement Antigens Apoptosis Apoptotic Area Autoimmunity Automobile Driving BIM Bcl-2-binding protein Biochemical Bone Marrow Bortezomib Cell Death Cell Survival Cell physiology Cellular biology Cessation of life Chronic Data Disease Drug resistance Drug usage Family member Flow Cytometry Fostering Gene Expression Gene Expression Profile Genes HIF1A gene Homeostasis Human Hypoxia Immunoglobulin-Secreting Cells Induction of Apoptosis Isoantibodies Life MCL1 gene Maintenance Mediating Memory B-Lymphocyte Mitochondria Mus Mutation Natural Resistance Natural Selections Organ Pathway interactions Patients Pharmaceutical Preparations Plasma Cells Plasma Enhancement Play Population Proteasome Inhibition Proteasome Inhibitor Publishing Regulatory Pathway Reporter Resistance Resistance development Role Testing Tissue Donors Transplantation Work antagonist endoplasmic reticulum stress experience improved improved outcome ineffective therapies insight multicatalytic endopeptidase complex mutant novel novel strategies novel therapeutic intervention novel therapeutics prevent resistance mechanism response restraint success transcription factor transcriptomics

项目摘要

Abstract The induction of plasma cells that secrete antibodies against donor tissue alloantigens is a major barrier to successful transplantation. Moreover, because many plasma cells are exceptionally long-lived, the resulting antibody titers are exceptionally durable. Hence strategies are needed to eliminate long-lived plasma cells that generate allospecific antibodies. A current dominant strategy for depleting plasma cells centers on compounds that interfere with the proteasome. Plasma cells are thought to uniquely require proteasome function to survive. However, for reasons unclear, substantial numbers of allospecific plasma cells resist the action of available proteasome inhibitors (PIs). This issue is compounded by the possibility that newly formed plasma cells, induced by persisting antigens, also contribute substantial amounts of deleterious antibodies. The chief objective of this project is to establish the impact of PIs on newly formed versus long-lived plasma cells, and define how biochemical responses to hypoxia affect mitochondrial apoptosis regulate responses of plasma cells to proteasome blockade. This work will leverage our unique capacity to resolve and characterize newly formed versus long-lived plasma cells. Specifically, we will: 1) Contrast the impact of PIs on newly formed versus long-lived PCs. 2) Test whether hypoxic niches and HIF1-alpha enhance PC resistance to PIs, and 3) Identify PI-induced mitochondrial death and resistance mechanisms in long-lived PCs. These studies will provide unique and needed insights into the mechanisms whereby proteasome inhibition affects allospecific plasma cell survival and function.

抽象的诱导浆细胞分泌针对供体组织同种抗原的抗体移植成功的主要障碍。此外，由于许多浆细胞由于寿命特别长，产生的抗体滴度特别持久。因此需要采取策略来消除产生同种异体特异性的长寿命浆细胞抗体。目前消耗浆细胞的主要策略集中在干扰蛋白酶体的化合物。浆细胞被认为具有独特的需要蛋白酶体功能才能生存。然而，由于不明原因，实质性大量同种异体浆细胞抵抗现有蛋白酶体抑制剂的作用（PI）。这个问题因新形成的浆细胞的可能性而变得更加复杂，由持久性抗原诱导，也会产生大量有害物质抗体。该项目的主要目标是确定 PI 对新的影响形成的浆细胞与长寿命的浆细胞，并定义生化反应如何缺氧影响线粒体凋亡调节浆细胞的反应蛋白酶体阻断。这项工作将利用我们独特的能力来解决和表征新形成的浆细胞与长寿命的浆细胞。具体来说，我们将：1）对比 PI 对新形成的 PC 和长寿命 PC 的影响。 2）测试是否缺氧生态位和 HIF1-α 增强 PC 对 PI 的抵抗力，以及 3) 识别 PI 诱导的长寿 PC 中的线粒体死亡和抵抗机制。这些研究将为蛋白酶体抑制机制提供独特且必要的见解影响同种异体浆细胞的存活和功能。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of invivo CXCR4 blockade and proteasome inhibition on bone marrow plasma cells in HLA-sensitized kidney transplant candidates.

体内 CXCR4 阻断和蛋白酶体抑制对 HLA 致敏肾移植候选者骨髓浆细胞的影响。

DOI：
发表时间：
2023-06
期刊：
影响因子：
0
作者：
Rossi, Amy P;Tremblay, Simon;Castro;Burg, Ashley A;Roskin, Krishna M;Gehman, Jenna M;Rike;Alloway, Rita R;Brailey, Paul;Allman, David;Hildeman, David A;Woodle, E Steve
通讯作者：
Woodle, E Steve

The Proteasome Inhibitor Bortezomib Induces p53-Dependent Apoptosis in Activated B Cells.

蛋白酶体抑制剂 Bortezomib 可诱导激活的 B 细胞发生 p53 依赖性细胞凋亡。