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: 10013606
• 负责人: Jonquil M Poret
• 金额: $ 3.74万
• 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/10013606
• 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 此露丝·柯希斯坦（Ruth L. Kirschstein）NRSA F31多样性应用的目标是增强A 年轻的未来酒精研究人员。这个奖学金机会还将为申请人提供研究培训 需要进行高优先级艾滋病毒/艾滋病相关的研究。申请人将获得研究技能 将酒精介导的代谢功能障碍集中在慢性Benge高度相关的临床前模型中 酒精（CBA）和猿猴免疫缺陷病毒（SIV）感染。与之相处的人的高风险酒精 艾滋病毒（PLWH）几乎是普通人群的两倍。此外，慢性高危酒精使用和HIV/SIV都是 与组织损伤独立相关，包括脂肪组织损伤。我们实验室的先前工作 使用SIV模型表明CBA给药会下降脂肪衍生的干细胞的分化 （ADSC），改善脂肪细胞细胞的大小并增加胶原蛋白的沉积和炎症细胞浸润 无症状的男性猕猴。但是，据我们所知，以前没有研究 CBA诱导的脂肪组织刚度对脂肪细胞代谢能力和功能的影响 SIV/HIV。科学文献和我们以前的研究中的报告支持了CBA- 诱导的肾上腺脂肪组织（OMAT）刚度是通过细胞外基质（ECM）失调介导的 SIV+恒河猕猴中促进脂肪细胞代谢失调的组成。提出的研究 作为申请人培训计划的一部分，将使用综合方法来评估以下方式 具体目的：1）检验以下假设：CBA介导的OMAT促纤维环境是由于失衡而导致的 ECM合成和SIV感染的猕猴中的降解和2）检验纤维化ECM的假设 从SIV感染的猕猴分离出的ADSC的代谢能力降低。提议的发现 研究将在SIV和 酒精并将为未来的翻译研究奠定基础。完成拟议的研究和 培训将促进申请人在酒精引起的领域的独立研究人员的发展 代谢失调。