Innate Inflammatory Control of Cachexia

恶病质的先天炎症控制

• 批准号: 10818772
• 负责人: Sarah E. Ewald
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818772
• 关键词: Animal Model; Animals; Automobile Driving; Cachexia; Chronic; Chronic Disease; Clinical Research; Complex; Disease; Endothelial Cells; Etiology; Fatigue; Fibroblasts; Fibrosis; Functional disorder; Human; IL1R1 gene; Immune signaling; Infection; Inflammatory; Interleukin-1; Lipids; Liver; Longevity; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Pathology; Patients; Perivascular Fibrosis; Role; Signal Transduction; Symptoms; Taxes; Therapeutic Intervention; Toxoplasma; cell type; chronic infection; combat; cost; debilitating pain; efficacious intervention; improved; lean body mass; lipid metabolism; mortality; novel; novel therapeutics; protective pathway; therapeutic evaluation; tool

Project Summary Cachexia, or the inflammatory loss of lean body mass, is a leading predictor of morbidity across chronic diseases. A disease of complex etiology, cachexia has proven difficult to model in animals. Little is known regarding the molecular mechanisms controlling cachexia onset, persistence and pathology; and widely efficacious interventions to reverse cachexia are lacking. We have recently shown that Toxoplasma infection in mice is novel animal model to study sustained cachexia. The longevity of this model has led to the discovery that chronically cachectic mice have perivascular fibrosis in the liver. Importantly, we have found that mice defective in the IL-1 innate immune signaling pathway are protected from cachexia and fibrosis and altered lipid metabolism, despite harboring a similar titer of Toxoplasma as WT animals. We hypothesize that cachexia is a cost of long-term IL-1 signaling. In this proposal we will determine whether eliminating chronic infection or blocking fibrosis is sufficient to reverse cachexia. We will identify the IL-1R expressing cell types driving cachexia and determine how IL-1 signaling on fibroblasts and/or endothelial cells control aberrant lipid metabolism in cachectic livers. Our studies are timely, as a recent clinical study demonstrated that blocking human IL-1a with a monoclonal antibody has reversed some symptoms of cachexia. Thus, we have a novel model to understand the mechanism of IL-1 function in cachexia and test therapeutic interventions for disease reversal. Understanding the role of the IL-1 axis in cachexia will improve the life span and comfort of patients suffering from a wide range of debilitating chronic diseases.

项目摘要 恶病质或瘦体重的炎症性损失是慢性疾病发病率的主要预测因素。 恶病质是一种病因复杂的疾病，已证明难以在动物中建模。关于这一点，我们知之甚少。 控制恶病质发作、持续和病理的分子机制;并且广泛有效 缺乏逆转恶病质的干预措施。我们最近发现，小鼠弓形虫感染是 研究持续性恶病质的新动物模型。这个模型的长期存在使我们发现， 慢性恶病质小鼠在肝脏中具有血管周围纤维化。重要的是，我们发现有缺陷的老鼠 在IL-1先天免疫信号传导途径中， 尽管携带与WT动物相似的弓形虫滴度，但在代谢方面，我们假设恶病质是 长期IL-1信号传导的代价。在这项提案中，我们将确定是否消除慢性感染或 阻断纤维化足以逆转恶病质。我们将确定驱动恶病质的IL-1 R表达细胞类型 并确定成纤维细胞和/或内皮细胞上的IL-1信号传导如何控制在糖尿病中的异常脂质代谢。 恶病质的肝脏我们的研究是及时的，因为最近的临床研究表明，用 一种单克隆抗体已经逆转了恶病质的某些症状。因此，我们有一个新的模型来理解 IL-1在恶病质中的作用机制和测试疾病逆转的治疗干预。理解 IL-1轴在恶病质中的作用将改善患者的寿命和舒适度， 慢性疾病的威胁

项目成果

Automated Spatially Targeted Optical Microproteomics (autoSTOMP) to Determine Protein Complexity of Subcellular Structures.

• DOI: 10.1021/acs.analchem.9b04396
• 发表时间: 2020-01-21
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: Yin B;Mendez R;Zhao XY;Rakhit R;Hsu KL;Ewald SE
• 通讯作者: Ewald SE

T. gondii infection induces IL-1R dependent chronic cachexia and perivascular fibrosis in the liver and skeletal muscle.

• DOI: 10.1038/s41598-020-72767-0
• 发表时间: 2020-09-24
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Melchor SJ;Hatter JA;Castillo ÉAL;Saunders CM;Byrnes KA;Sanders I;Abebayehu D;Barker TH;Ewald SE
• 通讯作者: Ewald SE

Inducible nitric oxide synthase (iNOS) is necessary for GBP-mediated T. gondii restriction in murine macrophages via vacuole nitration and intravacuolar network collapse.

诱导型一氧化氮合酶 (iNOS) 对于 GBP 介导的弓形虫通过液泡硝化和液泡内网络崩溃对小鼠巨噬细胞的限制是必需的。

• DOI: 10.1101/2023.07.24.549965
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Zhao,Xiao-Yu;Lempke,SamanthaL;UrbánArroyo,JanC;Yin,Bocheng;Holness,NadiaK;Smiley,Jamison;Ewald,SarahE
• 通讯作者: Ewald,SarahE

Tricarboxylic acid (TCA) cycle, sphingolipid, and phosphatidylcholine metabolism are dysregulated in T. gondii infection-induced cachexia.

• DOI: 10.1016/j.heliyon.2023.e17411
• 发表时间: 2023-07
• 期刊: HELIYON
• 影响因子: 4
• 作者: Feng, Tzu-Yu;Melchor, Stephanie J.;Zhao, Xiao-Yu;Ghumman, Haider;Kester, Mark;Fox, Todd E.;Ewald, Sarah E.
• 通讯作者: Ewald, Sarah E.

Cellular barcoding of protozoan pathogens reveals the within-host population dynamics of Toxoplasma gondii host colonization.

• DOI: 10.1016/j.crmeth.2022.100274
• 发表时间: 2022-08-22
• 期刊: Cell reports methods