Role of GDF15 in the Regulation of Host Tolerance to Inflammation

GDF15 在调节宿主炎症耐受性中的作用

基本信息

批准号：
10554353
负责人：
Ruslan Medzhitov
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
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：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554353
关键词：
Ablation Acute Affect Antibodies Autoimmunity B-Cell Activation Bone Marrow Cardiomyopathies Cardiotoxicity Cells Cellular Stress Circulation Communication Data Disease Endocrine Enhancers Functional disorder GDF15 gene GDNF receptors Growth Factor Growth Factor Receptors Heart Heart failure Hormones Hour Human Impairment Infection Inflammation Inflammatory Inflammatory Response Influenza Injury Intravenous Lead Ligands Light Lipopolysaccharides Macrophage Malignant Neoplasms Mediating Metabolic Metabolism Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus NF-kappa B Neoplasms Nerve Growth Factor Receptors Neuroglia Neurons Neurotransmitters Nonesterified Fatty Acids Nuclear Organ Organ failure Organism Oxidative Phosphorylation Pathway interactions Plasma Poly I-C Production Recombinant Growth Factor Regulation Reporting Role Sepsis Signal Transduction Source Starvation Stimulus Stress Structure of area postrema Testing Therapeutic Tissue Preservation Tissues Toll-like receptors Triglyceride Metabolism Triglycerides Xenobiotics acute infection attenuation cardioprotection cecal ligation puncture cytokine hemodynamics hindbrain hypothalamic-pituitary-adrenal axis improved in vivo intraperitoneal morphogens mortality nano nerve supply neuronal circuitry parabrachial nucleus pathogen prevent receptor response septic virtual

项目摘要

PROJECT SUMMARY Growth and Differentiation Factor 15 (GDF15) is highly induced in virtually all inflammatory conditions in humans, including sepsis, cancer and autoimmunity, but its role in the inflammatory response has been unclear. This proposal seeks to understand the role of Growth and Differentiation Factor 15 (GDF15) in mediating protection in sepsis. Preliminary data for this proposal reveals that GDF15 is induced specifically in models of acute infection/inflammation but not other environmental stress conditions and achieves nanogram levels in circulation. The GDF15 receptor, glial cell-lone derived neurotrophic factor receptor alpha-like (GFRAL), was found only in the hindbrain and not induced by inflammation. Blockade of GDF15 led to enhanced mortality in multiple models of sepsis, including lipopolysaccharide (LPS), cecal-ligation puncture (CLP), Poly(I:C), and influenza. Conversely, late administration of recombinant GDF15 led to protection. GDF15 inhibition did not affect inflammatory magnitude or pathogen control. However, GDF15 blockade led to an impairment in the ability of mice to switch to an oxidative phosphorylation state. There was no difference in ketonemia or plasma free fatty acids but a significant decrease in circulating plasma triglycerides. We also found that blockade of GDF15 led to enhanced cardiotoxicity, without a difference in overall hemodynamic control. Thus, GDF15 is a tissue protective hormone. This proposal seeks to test the idea that GDF15 is an adaptive cytokine produced by macrophages in response to acute inflammation, which mediates cardioprotection by controlling triglyceride metabolism via sympathetic innervation.

项目摘要生长和分化因子15（GDF15）在几乎所有炎症条件下都高度诱导人类，包括败血症，癌症和自身免疫性，但其在炎症反应中的作用一直是不清楚。该建议旨在了解增长和分化因子15（GDF15）在败血症中介导保护。该提案的初步数据表明，GDF15是在急性模型中专门诱导的感染/炎症，但没有其他环境压力状况，并在循环。 GDF15受体，神经胶质细胞衍生的神经营养因子受体α样（GFRAL）是仅在后脑脑中发现，而不是由炎症引起的。 GDF15的封锁导致死亡率提高败血症的多种模型，包括脂多糖（LPS），盲肠 - 绑定穿刺（CLP），poly（i：c）和流感。相反，重组GDF15的晚期给药导致了保护。 GDF15抑制没有影响炎症大小或病原体控制。但是，GDF15封锁导致小鼠切换到氧化磷酸化状态的能力。酮症或血浆没有差异游离脂肪酸，但循环血浆甘油三酸酯的显着降低。我们还发现 GDF15导致了增强的心脏毒性，没有整体血流动力控制差异。因此，GDF15是一个组织保护激素。该建议旨在测试GDF15是一种自适应细胞因子产生的想法巨噬细胞响应急性炎症，该炎症通过控制甘油三酸酯介导心脏保护通过同情神经的代谢。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induction of natural IgE by glucocorticoids.

DOI：
10.1084/jem.20220903
发表时间：
2022-10-03
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
通讯作者：

Tissue Biology: In Search of a New Paradigm.

组织生物学：寻找新范式。

DOI：
10.1146/annurev-cellbio-120420-113830
发表时间：
2023
期刊：
Annual review of cell and developmental biology
影响因子：
11.3
作者：
Adler,Miri;Chavan,ArunR;Medzhitov,Ruslan
通讯作者：
Medzhitov,Ruslan

Nutrient-derived signals regulate eosinophil adaptation to the small intestine.

DOI：
10.1073/pnas.2316446121
发表时间：
2024-01-30
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Kutyavin, Vassily I.;Korn, Lisa L.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan

Immune sensing of food allergens promotes avoidance behaviour.

DOI：
10.1038/s41586-023-06362-4
发表时间：
2023-08
期刊：
NATURE
影响因子：
64.8
作者：
Florsheim, Esther B.;Bachtel, Nathaniel D.;Cullen, Jaime L.;Lima, Bruna G. C.;Godazgar, Mahdieh;Carvalho, Fernando;Chatain, Carolina P.;Zimmer, Marcelo R.;Zhang, Cuiling;Gautier, Gregory;Launay, Pierre;Wang, Andrew;Dietrich, Marcelo O.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan

Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids.

脂联素和相关的 C1q/TNF 相关蛋白选择性地与阴离子磷脂和鞘脂结合。

DOI：
10.1073/pnas.1922270117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Ye,JessicaJ;Bian,Xin;Lim,Jaechul;Medzhitov,Ruslan
通讯作者：
Medzhitov,Ruslan