Role of MLKL in Alcohol-associated Liver Disease

MLKL 在酒精相关性肝病中的作用

• 批准号: 10369140
• 负责人: Xiaoqin Wu
• 金额: $ 17.03万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369140
• 关键词: Acute; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Anti-Inflammatory Agents; Apoptotic; Bone Marrow; Bone Marrow Transplantation; Cell Culture Techniques; Cell Death; Cell Survival; Cell model; Cells; Cessation of life; Chimera organism; Chronic; Cirrhosis; Clinical; Communication; Complex; Data; Development; Development Plans; Disease; Disease Progression; Environment; Equilibrium; Ethanol; Exhibits; Exposure to; Foundations; Functional disorder; Future; Heavy Drinking; Hepatic; Hepatitis; Hepatocyte; Heterogeneity; Histone H3; Homeostasis; Human; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knock-out; Kupffer Cells; Liver; Liver diseases; Maintenance; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Myeloid Cells; Natural Immunity; Necrosis; Paper; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phenotype; Phosphotransferases; Play; Population; Positioning Attribute; Primary carcinoma of the liver cells; Process; Productivity; RIPK1 gene; RIPK3 gene; Regulation; Research; Research Personnel; Resolution; Role; S100A8 gene; Signal Transduction; Solid; Stains; Technical Expertise; Testing; Therapeutic Intervention; Tissues; Training; United States; Work; alcohol exposure; alcohol response; career; career development; design; extracellular; in vivo; injury and repair; insight; liver inflammation; macrophage; monocyte; mortality; mouse model; neutrophil; phosphoproteomics; prevent; professor; programs; recruit; response; response to injury; restoration; skill acquisition; socioeconomics; tissue injury

Project summary The Candidate is a young investigator dedicated to developing an academic career focused on understanding the mechanisms by which ethanol disrupts balance between immune cell survival and death pathways. With a strong background in liver diseases and related innate immunity, the candidate has developed particular expertise in the use of in vivo and cell culture models to conduct the proposed studies. The Candidate’s current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development Plan outlines 2-years of mentored training on technical skills and career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position is also outlined. The Candidate’s Mentor has a proven track-record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her lab. Research plan: Alcohol-associated liver disease (ALD) remains a major socioeconomic burden with high morbidity and mortality. Activation of innate immunity not only contributes to progression of ALD, but is also critical for resolution of injury. Appropriate regulation of pro-survival and pro-death pathways is critical to the ability of innate immune cells to rapidly respond to maintain liver homeostasis in ethanol-induced injury. MLKL-mediated necroptosis plays a dual role in tissue injury/repair. Whether MLKL-mediated necroptosis of immune cells is beneficial or detrimental in the context of ethanol is unknown. In preliminary work, Mlkl deficiency in myeloid cells exacerbated ethanol-induced injury, associated with increased ethanol-induced accumulation of hepatic macrophages and neutrophils. Importantly, we found that Gao-binge increased necrosis/necroptosis of hepatic F4/80+ cells, suggesting that MLKL may protect from ethanol-induced injury by promoting macrophage death and resolution of inflammation. Together, these data led us to hypothesize that myeloid cell-specific MLKL restricts ethanol- induced injury by regulating hepatic immune cell survival and death. To test this hypothesis, hepatic immune cell populations and death will be characterized by flow cytometric analysis of isolated NPCs from livers of Mlkl BM chimeras after Gao-binge. We will then challenge cell-specific knock-outs (LysM, Clec4f and MRP8 CRE crossed with Mlklfl/fl) to ethanol, to distinguish cell-specific contributions of MLKL to mALD. Further, a phospho-proteomics paired with targeted mechanistic approaches will be utilized to determine whether ethanol-mediated activation of MLKL is RIP3-dependent and/or RIP3-independent. Additionally, since neutrophils and neutrophil extracellular traps (NETs) are important in ALD, the project will further explore whether neutrophil-specific MLKL limits ethanol-induced injury by regulating NETs. Altogether, this proposal will provide a solid foundation for future mechanistic studies and clinical interventions for ethanol-induced injury and inflammation.

项目总结