Protein Glycosylation in the Coagulopathy and Inflammation of Sepsis

脓毒症凝血障碍和炎症中的蛋白质糖基化

• 批准号: 10641837
• 负责人: JAMEY MARTH
• 金额: $ 267.64万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641837
• 关键词: Address; Age; Alkaline Phosphatase; Biological Markers; Blood; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Cause of Death; Cell surface; Cessation of life; Clinical; Core Facility; Data; Data Analyses; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease stratification; Endothelium; Experimental Models; Factor XI; Frequencies; Functional disorder; Galactose; Genetic; Glycocalyx; Glycoproteins; Glycoside Hydrolases; Goals; Half-Life; Health; Health Care Costs; Hemostatic function; Heparitin Sulfate; Hepatocyte; Human; Hyaluronan; Hyaluronic Acid; Immune response; Incidence; Infection; Inflammation; Innate Immune Response; Intensive Care Units; Interleukin-10; Investigation; Knowledge; Kupffer Cells; Lectin; Lectin Receptors; Life; Link; Macrophage; Malignant Neoplasms; Membrane Glycoproteins; Molecular; Neuraminidase; Organ; Outcome; Pathogenesis; Patients; Peer Review; Plasma; Polysaccharides; Process; Prognosis; Protein Glycosylation; Proteins; Proteome; Proteomics; Protocols documentation; Publications; Regulation; Research; Role; Salmonella; Sampling; Scientist; Sepsis; Serology; Serum; Severity of illness; Stratification; Survivors; Syndrome; Therapeutic; Thrombosis; Tissues; Urine; Vascular System; Vascular remodeling; Virulence; biomedical scientist; comparative; data acquisition; disability; disease prognosis; effective therapy; experience; experimental analysis; human disease; hypoperfusion; insight; microorganism; mortality; novel; novel marker; novel strategies; pathogen; pathogenic bacteria; patient prognosis; prognostic; programs; receptor; senescence; septic patients; vascular factor

SUMMARY Sepsis is life-threatening syndrome caused by the presence of harmful microorganisms in the blood and tissues and resulting in host inflammation, coagulopathy and organ dysfunction. As the leading cause of death in non-cardiac intensive care units, the incidence of sepsis continues to increase while no new effective therapies have been developed in decades. Among patients, mortality averages 25%, while many survivors experience long-term disabilities caused by thrombosis, hypoperfusion, and hyperinflammation. Globally, sepsis is more prevalent than cancer with millions of patients and billions of dollars of health care costs annually. Lack of molecular information of the pathophysiology of sepsis has primarily contributed to the paucity of new and more effective treatments. This program project renewal proposal continues to address this problem with novel approaches to advance the knowledge of sepsis from a descriptive to a more molecular basis. The program retains the expertise of scientists and clinicians whom together are making transformative discoveries of disease mechanisms and protective strategies targeted by the pathogen and the host in the onset and progression of sepsis. The proposed program renewal leverages comparative models of experimental sepsis applied to the discovery of disease mechanisms that rapidly remodel and regulate host blood and vascular components. Remodeling includes glycosidic and proteolytic processes that cause profound changes to the half-lives, localization, abundance, and functions of circulating and cell surface glycoproteins and platelets, linked to the coagulopathy, inflammation, and lethality of sepsis. The program is integrated by the overall hypothesis that Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. The three projects and four core facilities proposed will address this hypothesis with synergistic, interdisciplinary, and state-of-the-art approaches. Aims of the projects and cores encompass comparative molecular investigations of coagulation factors, tissue thrombosis, inflammation, serology, and pathogen burden and virulence among blood, urine, and tissue proteomes. Findings thus far have identified mechanisms that differentially identify and alter sepsis in the context of discrete pathogens including changes in pathogen virulence, supporting the emerging view that sepsis does not arise from a singular disease mechanism and may be stratified to achieve diagnostic and therapeutic benefits. Comparative analyses of experimental and human sepsis will continue as findings thus far have indicated conserved markers of disease mechanisms linked to stratification by pathogen and patient prognosis. The rationale for the aims of this program are derived from extensive supporting data and recent peer-reviewed publications. Additional discoveries that this program is poised to make will enable further advances in the mechanistic understanding of the life-threatening changes to host blood and vascular systems during sepsis and generate significant insights needed to develop more effective diagnostics and therapeutics.

总结

项目成果

Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia.

• DOI: 10.1128/msystems.00395-22
• 发表时间: 2022-08-30
• 期刊: mSystems
• 影响因子: 6.4

Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections.

• DOI: 10.1038/s41467-023-42572-0
• 发表时间: 2023-10-23
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Toledo, Alejandro Gomez;Bratanis, Eleni;Velasquez, Erika;Chowdhury, Sounak;Olofsson, Berit;Sorrentino, James T.;Karlsson, Christofer;Lewis, Nathan E.;Esko, Jeffrey D.;Collin, Mattias;Shannon, Oonagh;Malmstrom, Johan
• 通讯作者: Malmstrom, Johan

Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia.

• DOI: 10.1126/scitranslmed.abd6737
• 发表时间: 2021-03-24
• 期刊: Science translational medicine
• 影响因子: 17.1

Re-evaluation of FDA-approved antibiotics with increased diagnostic accuracy for assessment of antimicrobial resistance.

• DOI: 10.1016/j.xcrm.2023.101023
• 发表时间: 2023-05-16
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Heithoff, Douglas M.;Barnes, V. Lucien;Mahan, Scott P.;Fried, Jeffrey C.;Fitzgibbons, Lynn N.;House, John K.;Mahan, Michael J.
• 通讯作者: Mahan, Michael J.

Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice.

• DOI: 10.1038/s41418-021-00797-w
• 发表时间: 2021-11
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Jiang Y;Tang Y;Hoover C;Kondo Y;Huang D;Restagno D;Shao B;Gao L;Michael McDaniel J;Zhou M;Silasi-Mansat R;McGee S;Jiang M;Bai X;Lupu F;Ruan C;Marth JD;Wu D;Han Y;Xia L
• 通讯作者: Xia L