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.

抽象的。越来越多的证据表明脂肪组织是机制的中心，与年龄相关疾病，感染和代谢功能障碍的寿命，相关疾病的起源涉及的途径。脂肪组织功能障碍及其全身效应的一个过程是细胞感应。这是众所周知，感觉细胞在肥胖症和衰老中积聚在脂肪组织中。但是，引起脂肪组织中细胞感应的机制仍然难以捉摸，在该领域的更多研究是需要开发有效的鼻溶液疗法。细胞外基质（ECM）的重塑是必不可少的用于健康的脂肪组织形成和可塑性。 ECM为细胞，但它还通过与细胞表面整合素的结合和 Syndecans。由于其关键功能，需要“健康细胞”与ECM的附着细胞增殖和存活以及缺乏细胞ECM接触会导致细胞死亡。但是，其他策略，例如，在没有ECM接触的情况下，该细胞使用自噬激活来生存。我们报道 Syndecan（SDC）基因的突变降低了能量代谢和果蝇果蝇的寿命 Melanogaster。我们还发现，脂肪体中SDC表达降低的苍蝇的磷酸化较低 Akt的水平，一种自噬的调节剂，但也增加了脂肪水平，并且比饥饿更具抵抗力控件。此外，脂肪特异性的SDC敲低苍蝇显示出血管紧张素的较高表达转化酶相关的基因。哺乳动物脂肪细胞表达肾素 - 血管紧张素的成分系统（RAS）和局部RAS的延长激活会增加氧化应激，并触发细胞在几个组织/器官细胞中的感应。根据这些观察结果和我们的发现，我们假设是脂肪组织中SDC活性的缺乏促进自噬以维持细胞和组织在没有细胞ECM接触的情况下，体内平衡。但是，最终在年轻人中的生存策略通过激活RAS诱导的细胞感应而导致脂肪组织功能障碍和加速衰老。为了检验我们的假设并开始描述SDC调节自噬和的机制细胞感应，我们建议使用脂肪细胞特异性SDC4敲除（KO）小鼠。我们的初步研究证明全球和脂肪细胞特异性的SDC4 KO雌性小鼠的脂肪质量比对照组的脂肪量多。年轻，支持模型的可行性。该项目的发现可能会有重大翻译价值以来我们在人类中的遗传研究表明SDC4基因中的变体是相关的儿童的肥胖和甘油三酸酯水平的提高，并提高了可能性的可能性一百年纪念在一群健康的老年人中。还发现相同的遗传变异体重指数，高血压和冠状动脉疾病的患病率增加老年人，证实了SDC4在与年龄相关的表型中起关键作用的想法。

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）

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

DOI：
10.1161/circulationaha.121.056019
发表时间：
2022-01-04
期刊：
Circulation
影响因子：
37.8
作者：
Sreejit G;Nooti SK;Jaggers RM;Athmanathan B;Ho Park K;Al-Sharea A;Johnson J;Dahdah A;Lee MKS;Ma J;Murphy AJ;Nagareddy PR
通讯作者：
Nagareddy PR

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".

DOI：
10.1161/circulationaha.121.056679
发表时间：
2022-03-08
期刊：
Circulation
影响因子：
37.8
作者：
Nagareddy PR;Sreejit G
通讯作者：
Sreejit G

The Angiotensin-Converting Enzyme Inhibitor Lisinopril Mitigates Memory and Motor Deficits in a Drosophila Model of Alzheimer's Disease.

DOI：
10.3390/pathophysiology28020020
发表时间：
2021-06-18
期刊：
Pathophysiology : the official journal of the International Society for Pathophysiology
影响因子：
0
作者：
Thomas J;Smith H;Smith CA;Coward L;Gorman G;De Luca M;Jumbo-Lucioni P
通讯作者：
Jumbo-Lucioni P

Emerging roles of neutrophil-borne S100A8/A9 in cardiovascular inflammation.