Mesenteric Lymphatic / Perilymphatic Adipose Tissue Crosstalk; Mechanism of Alcohol Immunomodulation

肠系膜淋巴管/外淋巴管脂肪组织串扰；

• 批准号: 10189452
• 负责人: Flavia Moreira Souza
• 金额: $ 18.25万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189452
• 关键词: Acute; Address; Adipose tissue; Adult; Age; Alcohol consumption; Alcohols; American; Antibodies; Antigen-Presenting Cells; Antigens; Area; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; Chronic; Control Animal; Data; Dendritic Cells; Development; Development Plans; Elements; Ensure; Environment; Extravasation; Fatty acid glycerol esters; Functional disorder; Funding; Gastrointestinal tract structure; Gut Mucosa; Heavy Drinking; Immune; Immune system; Immunity; Impairment; In Vitro; Inflammatory Response; Injections; Insulin Resistance; Interleukin-6; Interruption; Intestinal Mucosa; Investigation; Link; Louisiana; Lymph; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic function; MAP2K1 gene; MAPK8 gene; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Metabolic; Molecular Target; National Institute on Alcohol Abuse and Alcoholism; Pathologic; Peripheral Blood Mononuclear Cell; Permeability; Phenotype; Positioning Attribute; Preparation; Proteins; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Role; Scientist; Structure; Supervision; T-Cell Proliferation; T-Lymphocyte; Testing; Tight Junctions; Tissues; Training; United States National Institutes of Health; Universities; Visceral; adiponectin; alcohol research; antimicrobial; binge drinking; career; career development; chronic alcohol ingestion; drinking; experience; faculty research; glucose uptake; immune function; immunoregulation; in vivo; inflammatory milieu; insight; insulin signaling; lymphatic circulation; lymphatic vessel; macromolecule; macrophage; mesenteric lymph node; mesenteric lymphatics; novel; novel strategies; p38 Mitogen Activated Protein Kinase; prevent; response; success

The NIH Mentored Research Scientist Development Award (K01) aims to ensure that a diverse pool of trained scientists is available to address nation's biomedical needs. This K01 Mentored Research Scientist Development Award application from a promising T-32 and F-32 funded early career investigator will provide support for an intensive, supervised career development experience through mentored research in preparation for transition to an academic research faculty position. The mentored research career development plan will focus on understanding the mechanisms of alcohol-mediated disruption of mesenteric lymphatic transport, lymphatic leakage, and the consequent alterations in perilymphatic adipose tissue (PLAT) functional phenotype. Specifically, the focus will be on how alcohol disrupts lymphatic integrity leading to lymphatic leakage of imunne cells into PLAT and the role of the PLAT immune cells on the development of IR, which is a new area of research to the candidate. Key elements of the candidate's research career development plan are: (1) to develop a research focus on the interaction between lymphatic immune cell leakage and PLAT immune cell role on insulin signaling and glucose uptake; (2) to establish how lymphatic leakage disrupts the immune dialog between intestinal mucosa and mesenteric lymph nodes; and (3) to develop expertise in alcohol- mediated immunometabolic consequences, particularly insulin resistance. The studies will focus on alcohol- induced lymphatic leakage via disruption of lymphatic endothelial tight junctions leading to PLAT IR and interrupting the immune dialog between intestinal mucosa and mesenteric lymph node. Three specific aims will test the predictions that a) alcohol induces lymphatic leakage via disruption of lymphatic endothelial tight junctions; b) alcohol-induced lymphatic leakage of immune cells into PLAT leads to increased fTregs expansion disrupting the immune dialog between gut and mesenteric lymph nodes (MLN); c) PLAT fTregs are responsible for PLAT IR. The proposed studies will combine in vivo with in vitro approaches to critically test the hypothesis. The successful completion of these studies will provide new insights, into the pathological mechanisms of alcohol-induced insulin resistance and will bring a novel approach that will link lymphatic function and PLAT with alcohol immunomodulation leading to insulin resistance. The scientific environment at Louisiana State University includes a NIAAA-funded Comprehensive Alcohol Research Center and outstanding facilities for the candidate's research. Along with an excellent mentor, this environment will ensure the accomplishments of the proposed studies and the successful transition of the candidate to an academic research faculty position.

美国国立卫生研究院指导研究科学家发展奖（K 01）的目的是确保一个多样化的人才库， 科学家可以满足国家的生物医学需求。K 01指导的研究科学家 发展奖申请从一个有前途的T-32和F-32资助的早期职业调查员将提供 通过在筹备过程中进行指导性研究，支持密集的、有监督的职业发展经验 过渡到一个学术研究教师的位置。指导研究职业发展计划将 专注于了解酒精介导的肠系膜淋巴转运中断的机制， 淋巴漏，以及随之而来的淋巴管外脂肪组织（PLAT）功能的改变 表型具体来说，重点将是如何酒精破坏淋巴完整性，导致淋巴 免疫细胞渗漏入PLAT和PLAT免疫细胞在IR发展中的作用，这是一个 新的研究领域的候选人。候选人的研究职业发展计划的关键要素是： (1)开展淋巴免疫细胞渗漏与血小板免疫相互作用的研究 细胞对胰岛素信号传导和葡萄糖摄取的作用;（2）确定淋巴渗漏如何破坏免疫系统， 肠粘膜和肠系膜淋巴结之间的对话;（3）发展酒精方面的专业知识- 介导的免疫代谢后果，特别是胰岛素抵抗。这些研究将集中在酒精- 通过破坏淋巴内皮紧密连接诱导淋巴渗漏，导致PLAT IR， 阻断肠粘膜与肠系膜淋巴结之间的免疫对话。三个具体目标将 测试以下预测：a）酒精通过破坏淋巴内皮细胞的紧密连接而诱导淋巴渗漏 连接; B）酒精诱导的免疫细胞淋巴渗漏进入PLAT，导致fT增加 扩张破坏肠道和肠系膜淋巴结（MLN）之间的免疫对话; c）PLAT fT 3是 拟议的研究将联合收割机体内与体外方法相结合，以严格测试 假说.这些研究的成功完成将提供新的见解， 酒精诱导的胰岛素抵抗的机制，并将带来一种新的方法，将淋巴 功能和PLAT与酒精免疫调节导致胰岛素抵抗。科学环境在 路易斯安那州立大学包括一个由NIAAA资助的综合酒精研究中心， 候选人的研究设施。沿着一位优秀的导师，这种环境将确保 建议研究的成就和候选人成功过渡到学术 研究员职位。