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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.

摘要

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.

DOI：
10.1016/j.ajt.2023.02.022
发表时间：
2023-06
期刊：
AMERICAN JOURNAL OF TRANSPLANTATION
影响因子：
8.8
作者：
Rossi, Amy P.;Tremblay, Simon;Castro-Rojas, Cyd M.;Burg, Ashley A.;Roskin, Krishna M.;Gehman, Jenna M.;Rike-Shields, Adele;Alloway, Rita R.;Brailey, Paul;Allman, David;Hildeman, David A.;Woodle, E. Steve
通讯作者：
Woodle, E. Steve

Advanced Genomics-Based Approaches for Defining Allograft Rejection With Single Cell Resolution.