Chronic binge alcohol in SIV infection: impact of adipose tissue stiffness on metabolic dysfunction

SIV 感染中的慢性酗酒：脂肪组织硬度对代谢功能障碍的影响

• 批准号: 10292429
• 负责人: Jonquil M Poret
• 金额: $ 3.79万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292429
• 关键词: AIDS/HIV problem; Actins; Adipocytes; Adipose tissue; Alcohol consumption; Alcohols; Animal Model; Cell Adhesion Molecules; Cell Communication; Cell Size; Cells; Chronic; Collagen; Collagen Fiber; Communication; Complement; Critical Thinking; Deposition; Development; Disintegrins; Elastin; Elastin Fiber; Environment; Enzymes; Experimental Designs; Extracellular Matrix; Extracellular Matrix Proteins; Fatty acid glycerol esters; Fellowship; Fibrillar Collagen; Fibronectins; Foundations; Functional disorder; Funding; Future; General Population; Genes; Glycoproteins; Goals; HIV; Health Sciences; Homeostasis; Impairment; In Vitro; Infiltration; Inflammatory; Influentials; Insulin; Laboratories; Leadership; Lipolysis; Literature; Liver; Louisiana; Macaca; Macaca mulatta; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Metalloproteases; Modeling; Molecular; National Institute on Alcohol Abuse and Alcoholism; National Research Service Awards; Oral; Pathology; Pathway Analysis; Pathway interactions; Persons; Physiology; Plasminogen Activator Inhibitor 1; Pre-Clinical Model; Protein-Lysine 6-Oxidase; Proteoglycan; Reporting; Research; Research Design; Research Personnel; Research Training; Resources; SIV; Scientist; Signal Transduction; Skeletal Muscle; Stains; Structure; Techniques; Testing; Tissues; Training; Universities; Virus Diseases; Work; alcohol effect; alcohol misuse; alcohol research; alcohol risk; alcohol use disorder; antiretroviral therapy; career; cell type; comorbidity; crosslink; culture plates; design; glucose uptake; in vivo; lipid biosynthesis; male; polydimethylsiloxane; pre-clinical; pre-doctoral; simian human immunodeficiency virus; skills; stem cell differentiation; stem cells; success; tissue injury; training opportunity; translational study

ABSTRACT The goal of this Ruth L. Kirschstein NRSA F31-Diversity application is to enhance the predoctoral training of a young future alcohol researcher. This fellowship opportunity will also provide the applicant with research training required to conduct High Priority HIV/AIDS-related research. The applicant will achieve skills to conduct research concentrated on alcohol-mediated metabolic dysfunction in the highly relevant preclinical model of chronic binge alcohol (CBA) and simian immunodeficiency virus (SIV) infection. At-risk alcohol use among people living with HIV (PLWH) is nearly twice that of the general population. Also, chronic at-risk alcohol use and HIV/SIV are both independently associated with tissue injury, including adipose tissue injury. Previous work from our laboratory using a SIV model indicates that CBA administration decreases differentiation of adipose derived stem cells (ADSC), decreased adipocyte cell size and increases collagen deposition and inflammatory cell infiltration in asymptomatic male macaques. However, to our knowledge, there have been no previous studies to investigate the impact of CBA-induced adipose tissue stiffness on adipocyte metabolic capacity and function in the context of SIV/HIV. Reports in the scientific literature and our previous studies support the central hypothesis that CBA- induced omental adipose tissue (OmAT) stiffness is mediated by dysregulation of extracellular matrix (ECM) composition promoting adipocyte metabolic dysregulation in SIV+ rhesus macaques. The proposed studies to be performed as part of the applicant’s training plan will utilize an integrated approach to assess the following Specific Aims: 1) Test the hypothesis that CBA-mediated OmAT pro-fibrotic milieu results from an imbalance in ECM synthesis and degradation in SIV-infected macaques and 2) Test the hypothesis that fibrotic ECM decreases metabolic capacity of ADSCs isolated from SIV-infected macaques. Findings from the proposed studies will provide a more comprehensive understanding adipose tissue dysfunction in the context of SIV and alcohol and will provide the foundation for future translational studies. Completion of the proposed research and training will facilitate the applicant’s progression to an independent researcher in the field of alcohol-induced metabolic dysregulation.

抽象的 Ruth L. Kirschstein NRSA F31-Diversity 应用程序的目标是加强博士前培训 年轻的未来酒精研究员。该奖学金机会还将为申请人提供研究培训 需要进行与艾滋病毒/艾滋病相关的高优先级研究。申请人将获得进行研究的技能 专注于高度相关的慢性暴食临床前模型中酒精介导的代谢功能障碍 酒精（CBA）和猿猴免疫缺陷病毒（SIV）感染。患有此类疾病的人群中存在饮酒风险 艾滋病毒感染者（PLWH）几乎是普通人群的两倍。此外，长期饮酒和 HIV/SIV 都是高危人群 与组织损伤（包括脂肪组织损伤）独立相关。我们实验室之前的工作 使用 SIV 模型表明 CBA 给药会降低脂肪干细胞的分化 (ADSC)，减少脂肪细胞大小并增加胶原沉积和炎症细胞浸润 无症状的雄性猕猴。然而，据我们所知，之前没有任何研究来调查 CBA 诱导的脂肪组织硬度对脂肪细胞代谢能力和功能的影响 SIV/HIV。科学文献中的报告和我们之前的研究支持以下中心假设：CBA- 诱导的网膜脂肪组织 (OmAT) 僵硬是由细胞外基质 (ECM) 失调介导的 促进SIV+恒河猴脂肪细胞代谢失调的组合物。拟议的研究 作为申请人培训计划的一部分进行将采用综合方法来评估以下内容 具体目标：1) 检验以下假设：CBA 介导的 OmAT 促纤维化环境是由于 感染 SIV 的猕猴中 ECM 的合成和降解以及 2) 检验纤维化 ECM 的假设 降低从 SIV 感染的猕猴中分离出的 ADSC 的代谢能力。拟议的调查结果 研究将提供更全面的了解 SIV 背景下的脂肪组织功能障碍和 酒精，并将为未来的转化研究奠定基础。完成拟议的研究和 培训将有助于申请人晋升为酒精诱发领域的独立研究员 代谢失调。