Epigenetic Modulation in Septic Immunosuppression

脓毒症免疫抑制中的表观遗传调节

基本信息

批准号：
10413821
负责人：
Chunbin Zou
金额：
$ 46.09万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413821
关键词：
Adult Anti-Inflammatory Agents Architecture Attenuated BCL2 gene Bacteria Bacterial Infections CASP3 gene Cell Death Cell model Cells Cessation of life Chromatin Data Disease Endotoxins Epigenetic Process Etiology F Box Domain Functional disorder Gram-Negative Bacteria Half-Life Human Immune Targeting Immune response Immunity Immunomodulators Immunosuppression Impairment In Vitro Infection Inflammatory Inflammatory Response Lead Leukocytes Life Light Link Lipopolysaccharides Longevity Lung Lymphocyte Lymphocyte Count Lymphopenia Mediating Modeling Molecular Molecular Profiling Mus Natural Immunity Nosocomial Infections Pathogenesis Patients Pharmacologic Substance Phase Play Pneumonia Prognosis Protein-Arginine N-Methyltransferase Proteins Risk Role SKP Cullin F-Box Protein Ligases Sepsis Spleen System T-Lymphocyte Time Ubiquitin United States Work adaptive immunity coactivator-associated arginine methyltransferase 1 epigenetic regulation exhaust gain of function human tissue in vivo in vivo Model lung injury lymphocyte proliferation microbial mouse model new therapeutic target novel novel therapeutics pathogen patient prognosis peripheral blood receptor recruit sepsis induced acute lung injury septic septic patients small molecule small molecule inhibitor small molecule therapeutics translational approach ubiquitin-protein ligase

项目摘要

Project summary A hallmark of septic immunosuppression is a reduced number of lymphocytes due to decreased lymphocyte proliferation and increased cell death. A low lymphocyte count referred to as lymphopenia underscores a poor prognosis for septic patients with lower bacterial clearance and second nosocomial infections and death. Epigenetics modulates chromatin architecture to regulate immunity. Despite its importance, the role of epigenetics in septic immunosuppression in terms of lymphopenia remains elusive. In this proposal, we identify that bacteria-elevated Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) is critical for lymphopenia in sepsis; depletion of PRMT4 or inhibition of PRMT4 may attenuate the bacteria-mediated lymphocyte death in cellular and mice models. Our preliminary study shows that bacteria increase PRMT4 at protein level in murine and human lymphocytes. Bacteria reduce an E3 ubiquitin ligase SCF-FBXO9 to promote PRMT4 protein stability and abundance in the cells that leads to lymphocyte death. Depletion of PRMT4 or inhibition of PRMT4 with small molecule reduces bacteria mediated lymphocyte death in cellular and mice septic models. These findings demonstrate an un-described role of a key chromatin modulator PRMT4 in lymphocyte death that may shed lights on novel therapeutic avenue in septic immunosuppression. Therefore, our central hypothesis is that bacteria elevates PRMT4 protein inhibiting its SCF-Fbxo9 mediated proteasomal degradation that causes substantial lymphocyte death to lead immunosuppression; thus inhibition of PRMT4 may attenuate bacteria-mediated lymphocyte death in septic immuno-suppression. To explore this hypothesis we propose the following aims: (i) to determine if bacteria derived endotoxin LPS elevates PRMT4 protein levels by reducing an E3 ubiquitin ligase SCF-Fbxo9; and (ii) to study if elevated PRMT4 leads to substantial lymphocyte death thereby inhibition of PRMT4 may attenuate bacteria-induced septic immunosuppression. These studies will establish the pathophysiological function of a chromatin modulator, PRMT4, as a new effector in lymphocyte death in sepsis. These studies will expand the conceptual groundwork for us to understand how epigenetic regulation plays a central role in the pathogenesis of septic immunosuppression. These studies may serve as a springboard for translational approaches eventually using small molecule therapeutics to target this immune modulator.

项目摘要化粪池免疫抑制的标志是淋巴细胞减少的淋巴细胞数量减少增殖并增加细胞死亡。低淋巴细胞计数称为淋巴细胞减少症强调了较差细菌清除率较低的化粪池患者的预后和第二次医院感染和死亡的预后。表观遗传学调节染色质结构以调节免疫力。尽管它的重要性，但在淋巴细胞减少方面，败血症免疫抑制的表观遗传学仍然难以捉摸。在此提案中，我们确定细菌高度蛋白精氨酸N-甲基转移酶4/共激活剂相关精氨酸甲基转移酶1（PRMT4/ CARM1）对于败血症中的淋巴细胞减少至关重要。 PRMT4的耗竭或抑制 PRMT4可以减弱细菌介导的细胞和小鼠模型中的淋巴细胞死亡。我们的初步研究表明，细菌在鼠和人类淋巴细胞中蛋白质水平上的PRMT4增加。细菌减少 E3泛素连接酶SCF-FBXO9，以促进细胞中PRMT4蛋白的稳定性和丰度淋巴细胞死亡。 PRMT4的耗竭或用小分子抑制PRMT4可减少介导的细菌细胞和小鼠化粪池模型中的淋巴细胞死亡。这些发现表明了钥匙的未描述的角色淋巴细胞死亡中的染色质调节剂PRMT4可能会在化粪池的新型治疗大道上发光免疫抑制。因此，我们的中心假设是细菌升高PRMT4蛋白抑制其 SCF-FBXO9介导的蛋白酶体降解，导致大量淋巴细胞死亡铅免疫抑制；因此，抑制PRMT4可能会减弱败血性细菌介导的淋巴细胞死亡免疫抑制。为了探讨这一假设，我们提出以下目的：（i）确定细菌是否存在衍生的内毒素LPS通过减少E3泛素连接酶SCF-FBXO9来提高PRMT4蛋白水平；（ii）到研究如果升高的PRMT4导致大量淋巴细胞死亡，从而抑制PRMT4可能会减弱细菌引起的化粪池免疫抑制。这些研究将确定A的病理生理功能染色质调节剂PRMT4作为败血症淋巴细胞死亡的新效应子。这些研究将扩大我们了解表观遗传调节如何在发病机理中起核心作用的概念基础化粪池免疫抑制。这些研究最终可能是转化方法的跳板使用小分子疗法来靶向该免疫调节剂。