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：
10215534
负责人：
David M Allman
金额：
$ 69.17万
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/10215534
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 Factor V Family member Flow Cytometry Fostering Gene Expression Gene Expression Profile Genes HIF1A gene Homeostasis Human Hypersensitivity Hypoxia Immunoglobulin-Secreting Cells Isoantibodies Life MCL1 gene Maintenance Mediating Memory B-Lymphocyte Mitochondria Mus Mutation Natural Resistance 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 base 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 success transcription factor transcriptomics

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 Factor V Family member Flow Cytometry Fostering Gene Expression Gene Expression Profile Genes HIF1A gene Homeostasis Human Hypersensitivity Hypoxia Immunoglobulin-Secreting Cells Isoantibodies Life MCL1 gene Maintenance Mediating Memory B-Lymphocyte Mitochondria Mus Mutation Natural Resistance 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 base 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 success transcription factor transcriptomics

展开

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.

抽象的分泌针对供体组织的抗体的等离子体细胞的诱导是成功移植的主要障碍。而且，因为许多浆细胞是产生的抗体滴度异常持久的寿命异常耐用。因此需要采取策略来消除产生高型的长期浆细胞抗体。当前耗尽浆细胞以耗尽浆细胞为中心的主要策略会干扰蛋白酶体的化合物。浆细胞被认为是唯一的需要蛋白酶体功能才能生存。但是，出于原因不清楚，实质性同种体质浆细胞的数量抵抗可用蛋白酶体抑制剂的作用（pis）。新形成的浆细胞的可能性使这个问题更加复杂由持续的抗原引起的，也贡献了大量有害抗体。该项目的主要目的是建立PI对新的影响形成与长寿命的浆细胞，并定义生化反应如何缺氧影响线粒体凋亡调节血浆细胞对蛋白酶体阻滞。这项工作将利用我们独特的解决能力和表征新形成的与长寿命的浆细胞。具体来说，我们将：1）对比PI对新形成的与长寿命PC的影响对比。 2）测试是否低氧壁ni和HIF1-Alpha增强了对PI的PC耐药性，3）鉴定PI诱导的PC 长寿命PC中的线粒体死亡和抗性机制。这些研究会提供对蛋白酶体抑制的机制的独特和必要的见解影响同种浆细胞的存活和功能。