Syndecan-4 as a molecular link between adipose tissue and aging

Syndecan-4 作为脂肪组织与衰老之间的分子联系

基本信息

批准号：
10232057
负责人：
MARIA DE LUCA
金额：
$ 18.56万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10232057
关键词：
Adipocytes Adipose tissue Adult Affect Age Aging American Anchorage-Independent Growth Anoikis Apoptosis Architecture Area Autophagocytosis Behavior Binding Blood Vessels Body mass index Cell Aging Cell Death Cell Proliferation Cell Survival Cell surface Cells Cellular Morphology Centenarian Child Complex Coronary Arteriosclerosis Data Development Disease Down-Regulation Drosophila genus Drosophila melanogaster Elderly Energy Metabolism Enzymes Estrogens Excision Extracellular Matrix Family Fasting Fat Body Fatty acid glycerol esters Female Focal Adhesion Kinase 1 Foundations Functional disorder Future Gene Deletion Genes Genetic study Glucose Health Hepatic High Fat Diet Homeostasis Human Hypertension Hypertriglyceridemia Hypertrophy Individual Inflammation Inflammatory Integrins Invertebrates Knock-out Knockout Mice Lead Light Link Liver Longevity MAP Kinase Gene Mammals Mediator of activation protein Metabolic Metabolic dysfunction Modeling Molecular Mus Mutation Obesity Organ Oxidative Stress Oxidative Stress Induction Pathway interactions Peptide Hydrolases Peptidyl-Dipeptidase A Phenotype Phosphorylation Plasma Play Prevalence Process Production Proteins Rattus Receptor Signaling Receptor, Angiotensin, Type 1 Renin-Angiotensin System Reporting Research Research Proposals Resistance Role STK11 gene Signal Pathway Signal Transduction Starvation Structure Testing Tissues Variant Vertebrates age related base chemokine cohort cytokine fasting plasma glucose fly genetic variant indexing insulin sensitivity knock-down lipoprotein lipase member metabolic phenotype middle age mouse model p38 Mitogen Activated Protein Kinase pleiotropism progenitor public health relevance senescence subcutaneous syndecan syndecan-4

项目摘要

ABSTRACT. A growing body of evidence suggests that adipose tissue is at the center of mechanisms and pathways involved in longevity, the genesis of age-related diseases, inflammation, and metabolic dysfunction. One process that is involved in adipose tissue dysfunction and its systemic effects is cellular senescence. It is well-recognized that senescent cells accumulate in adipose tissue in obesity and with aging. However, the mechanisms eliciting cellular senescence in adipose tissue remain elusive and more research in this area is needed to develop effective senolytic therapies. The remodeling of the extracellular matrix (ECM) is essential for healthy adipose tissue formation and plasticity. The ECM provides structural and anchoring support to the cells, but it also regulates many aspects of the cell’s dynamic behavior by binding to cell-surface integrins and syndecans. Because of its pivotal function, the attachment of “healthy cells” to the ECM is needed for correct cell proliferation and survival, and lack of cell-ECM contact can lead to cell death. However, other strategies, such as autophagy activation, are employed by the cell to survive in the absence of ECM contact. We reported that mutations in the Syndecan (Sdc) gene reduce energy metabolism and life span in the fruit fly Drosophila melanogaster. We also found that flies with reduced Sdc expression in the fat body had lower phosphorylation levels of Akt, a regulator of autophagy, but also increased fat levels and were more resistant to starvation than controls. Moreover, fat body-specific Sdc knockdown flies displayed higher expression of the Angiotensin converting enzyme-related gene. Mammalian adipocytes express components of the renin-angiotensin systems (RAS) and prolonged activation of local RAS increases oxidative stress and triggers cellular senescence in several tissue/organ cells. Thus, based on these observations and our findings in flies our hypothesis is that deficiency of Sdc activity in the fat tissue promotes autophagy to maintain cellular and tissue homeostasis in the absence of cell-ECM contact. However, this survival strategy in young individuals ultimately leads to fat tissue dysfunction and accelerated aging through activation of RAS-induced cellular senescence. To test our hypothesis and start delineating the mechanism (s) through which Sdc regulates autophagy and cellular senescence, we propose to use adipocyte-specific Sdc4 knockout (KO) mice. Our preliminary studies show that global and adipocyte-specific Sdc4 KO female mice have more total fat mass than controls at a young age, supporting the feasibility of the model. Findings from this project will likely have significant translational value since our genetic studies in humans showed that a variant in the SDC4 gene is associated with adiposity in children and with increased triglyceride levels and decreased likelihood to become centenarian in a cohort of healthy elderly individuals. The same genetic variant was also found associated to body mass index, hypertension, and increased prevalence of coronary artery disease in a cohort of middle- aged individuals, corroborating the idea that SDC4 plays a critical role in age-related phenotypes.

摘要：越来越多的证据表明脂肪组织是机制和机制的核心。涉及长寿、年龄相关疾病的发生、炎症和代谢功能障碍的途径。参与脂肪组织功能障碍及其全身效应的过程之一是细胞衰老。众所周知，随着肥胖和衰老，衰老细胞会在脂肪组织中积累。引起脂肪组织细胞衰老的机制仍然难以捉摸，该领域的更多研究正在进行中细胞外基质 (ECM) 的重塑对于开发有效的 senolytic 疗法至关重要。 ECM 为健康的脂肪组织形成和可塑性提供结构和锚定支持。细胞，但它还通过与细胞表面整合素结合来调节细胞动态行为的许多方面由于其关键功能，“健康细胞”附着在 ECM 上是正确的必要条件。细胞增殖和存活以及细胞-ECM 接触的缺乏可能导致细胞死亡。我们报道了细胞利用诸如自噬激活等在没有 ECM 接触的情况下生存的方法。 Syndecan (Sdc) 基因的突变会降低果蝇的能量代谢和寿命我们还发现脂肪体内 Sdc 表达减少的果蝇磷酸化程度较低。 Akt（一种自噬调节剂）的水平，但也增加了脂肪水平，并且比其他人更能抵抗饥饿此外，脂肪体特异性 Sdc 敲低果蝇显示出更高的血管紧张素表达。哺乳动物脂肪细胞表达肾素-血管紧张素成分。系统 (RAS) 和局部 RAS 的长期激活会增加氧化应激并触发细胞因此，基于这些观察和我们在果蝇中的发现。假设脂肪组织中 Sdc 活性的缺乏会促进自噬以维持细胞和组织然而，这种生存策略最终在没有细胞-ECM 接触的情况下实现。通过激活 RAS 诱导的细胞衰老，导致脂肪组织功能障碍并加速衰老。为了检验我们的假设并开始描述 Sdc 调节自噬和细胞衰老，我们建议使用脂肪细胞特异性 Sdc4 敲除 (KO) 小鼠。表明整体和脂肪细胞特异性 Sdc4 KO 雌性小鼠的总脂肪量比对照组更高年轻时，支持该模型的可行性的研究结果可能具有重大意义。翻译价值，因为我们对人类的遗传学研究表明 SDC4 基因的变异与儿童肥胖，甘油三酯水平升高，患肥胖症的可能性降低在一组健康老年人中也发现了相同的基因变异。中年人群队列中的体重指数、高血压和冠状动脉疾病患病率增加老年人，证实了 SDC4 在年龄相关表型中发挥关键作用的观点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Towards an understanding of the mechanoreciprocity process in adipocytes and its perturbation with aging.

了解脂肪细胞中的机械互易过程及其随衰老的扰动。

DOI：
发表时间：
2021
期刊：
影响因子：
5.3
作者：
De Luca, Maria;Mandala, Maurizio;Rose, Giuseppina
通讯作者：
Rose, Giuseppina

Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.

NLRP3 炎症小体引发的中性粒细胞在骨髓中的保留对于心肌梗塞诱导的粒细胞生成至关重要。

DOI：
发表时间：
2022-01-04
期刊：
影响因子：
37.8
作者：
Sreejit, Gopalkrishna;Nooti, Sunil K;Jaggers, Robert M;Athmanathan, Baskaran;Ho Park, Ki;Al;Johnson, Jillian;Dahdah, Albert;Lee, Man K S;Ma, Jianjie;Murphy, Andrew J;Nagareddy, Prabhakara R
通讯作者：
Nagareddy, Prabhakara R

Letter by Nagareddy and Sreejit Regarding Article, "Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease".

Nagareddy 和 Sreejit 关于文章“Interleukin-1α 是心肌梗塞和慢性肾脏病中白细胞内皮粘附的中央调节剂”的信函。