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Biochemical Mechanisms for Sustained Humoral Immunity

持续体液免疫的生化机制

基本信息

批准号：
10637251
负责人：
David M Allman
金额：
$ 64.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-23 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637251
关键词：
ATF6 gene Acute Aftercare Alleles Antibodies Antibody Response Antibody titer measurement Apoptosis Apoptotic Autoantibodies Autoimmunity B-Lymphocytes Binding Biochemical Blood Vessels Bone Marrow Bone Marrow Cells Cations Cell Death Cell Survival Cell physiology Cells Connexins Cre driver Cues Data Disease Elements Endothelial Cells Endothelium Exposure to Family Fostering Health Homeostasis Homing Host Defense Human Humoral Immunities Immunoglobulin A Immunoglobulin G In Situ In Vitro Infection Longevity Mammals Mediating Metabolic Mitochondria Modeling Mutagenesis Mutation Newborn Infant Osteoblasts Outcome Pathogenicity Pathway interactions Pharmaceutical Preparations Plasma Cells Play Process Protein Biosynthesis Purinoceptor Regulation Role Serum Signal Transduction Source Spleen Stromal Cell-Derived Factor 1 Testing Transplantation Vaccination Vaccines Work XBP1 gene bone bone loss cell type chemokine endoplasmic reticulum stress extracellular improved improved outcome inhibitor insight novel strategies prevent response restraint transcription factor CHOP

项目摘要

Project summary Antibody-secreting plasma cells play critical roles in health and disease, yet little is known about the biochemical mechanisms controlling antibody synthesis and secretion or how these pathways intersect with pathways controlling cell survival. Furthermore, due to the high metabolic demands inherent to robust antibody secretion and the tendency for many plasma cells to persist for decades, pathways restraining apoptosis in plasma cells are likely to be integrated in unique ways. This project centers on the hypothesis that long- lived plasma cells in bone marrow obtain requisite signals to maintain antibody secretion and avoid cell death by sensing extracellular ATP with a purinergic receptor known as P2rX4. We further hypothesize that eATP is produced locally in the bone marrow for plasma cells by osteoblastic cells via the gap junction protein known as Panx3. Thus, consistent with our preliminary data, inhibition of P2rX4 or Panx3 function is predicted to cause the depletion of long-lived plasma cells and reduce serum antibody titers including for disease-associated antibodies. To test our hypothesis, we will: 1) Define cell intrinsic P2rX4-regulated outcomes for newborn and long-lived plasma cells, and 2) Define cell extrinsic sources and outcomes for eATP/Panx3 regulation of long-lived plasma cells. These studies will provide unique and needed insights into the specialized survival mechanisms employed by long-lived plasma cells. This work supports our long-term objective of developing strategies to effectively and specifically disable or deplete problematic plasma cells.

项目摘要分泌抗体的浆细胞在健康和疾病中起着关键作用，但知之甚少关于控制抗体合成和分泌的生化机制，这些途径与控制细胞存活的途径交叉。而且因为强抗体分泌所固有的高代谢需求以及许多抗体分泌的趋势，浆细胞持续几十年，抑制浆细胞凋亡的途径是可能会以独特的方式整合。这个项目的核心假设是，长期- 骨髓中的活浆细胞获得维持抗体分泌所必需的信号并通过嘌呤能受体感知细胞外ATP来避免细胞死亡， P2 rX4。我们进一步假设eATP是在骨髓中局部产生的，浆细胞通过称为Panx 3的差距连接蛋白被成骨细胞吸收。因此，在本发明中，与我们的初步数据一致，预测P2 rX 4或Panx 3功能的抑制导致长寿命浆细胞的消耗并降低血清抗体滴度，包括用于疾病相关抗体。为了验证我们的假设，我们将：1）定义细胞内在新生和长寿浆细胞的P2 rX 4调节结果，以及2）定义细胞 eATP/Panx 3调节长寿浆细胞的外在来源和结果。这些研究将提供独特的和必要的见解，专门生存长寿命浆细胞的机制。这项工作支持我们的长期目标，以有效和具体地有问题的浆细胞