ADAR2 and Adipose Dysfunction in Aging

ADAR2 和衰老过程中的脂肪功能障碍

• 批准号: 8958423
• 负责人: Nalini Santanam
• 金额: $ 35.69万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958423
• 关键词: 3' Untranslated Regions; Adenosine; Adipocytes; Adipose tissue; Age; Aging; Binding; Biogenesis; Biology; CCAAT-Enhancer-Binding Proteins; Cardiovascular Diseases; Cell physiology; Centenarian; Complex; DRADA2b protein; Data; Dementia; Diabetes Mellitus; Disease; Double-Stranded RNA; Endocrine Glands; Enzymes; Epigenetic Process; Family; Fatty acid glycerol esters; Functional disorder; Gene Targeting; Genetic; Genetic Transcription; Goals; Human; Hybrids; Impairment; Inosine; Insulin Resistance; Intervention; Knowledge; Lead; Light; Link; Lipids; MAPK7 gene; Malignant Neoplasms; Marshal; Mediating; Messenger RNA; Metabolic; MicroRNAs; Modeling; National Institute on Aging; Norway; Nucleotides; Obesity; Osteoblasts; Osteocytes; PPAR gamma; Pathology; Pathway interactions; Phenotype; Play; Post-Transcriptional Regulation; Process; Proteins; Publishing; RNA; RNA Editing; Rattus; Regulation; Research; Research Training; Risk; Role; Stem cells; Testing; Time; Tissues; Translations; Universities; Untranslated RNA; Visceral; adipocyte differentiation; age related; aged; blood glucose regulation; cardiometabolic risk; dsRNA adenosine deaminase; epigenetic regulation; experience; gain of function; human disease; improved; innovation; loss of function; malignant neurologic neoplasms; mortality; nervous system disorder; new therapeutic target; novel; osteoblast differentiation; osteogenic; prevent; public health relevance; targeted treatment; therapeutic target; undergraduate research

 DESCRIPTION (provided by applicant): Aging is a complex process that involves continuous accumulation of cellular damage. Interventions to prevent these damages will improve aging related pathologies. Adipose dysfunction increases with age, which dramatically alters fat mass, redistribution and function, leading to metabolic imbalance and increased risk to cardiometabolic diseases. Continuous turnover of adipose cells and thus recruitment of new pre-adipocytes (or adipose derived stem cells) and adipocytes is essential in maintaining adipose mass and function. Our recent studies showed age-dependent dysfunction in fat depots attributed to inability of pre-adipocytes to differentiate into adipocytes with aging due to de-regulation of adipogenic microRNAs (miRNAs). Pre-adipocyte differentiation is regulated by both genetic and epigenetic mechanisms. Understanding this phenomenon is important, since it will help (i) to better understand the relationship between the aging phenotype and adipose dysfunction and (ii) identify targets to treat or prevent cardiometabolic diseases that are associated with aging. Adenosine Deaminase acting on RNAs (ADAR) family of enzymes are key in post-transcriptional regulation and essential for RNA and protein diversity through RNA editing. Loss of ADARs resulted in increased mortality in US centenarians, increased risk to age-associated neurological diseases such as dementia and certain cancers. Loss of ADAR also resulted in increased obesity and insulin resistance. ADARs are currently explored as a good therapeutic target for certain neurological diseases and cancer. We hypothesize a loss of ADARs with aging plays a role in the observed age-mediated adipose dysfunction. We will test this hypothesis by proposing three aims. Our studies will use pre-adipocytes isolated from the visceral fat of young Fischer 344 x Brown Norway hybrid rats (6mo) compared to aged FBN rats (14mo, 24mo, 30mo). These rats are similar to humans and develop adiposity and insulin resistance with increasing age. AIM 1: To demonstrate the role for ADARs in the miRNA regulation of adipose function in aging. The goal of this aim is to investigate if ADAR expression and activity are altered with aging and it plays a role in the impairment of adipogenic miRNA and adipose function. AIM 2: To demonstrate that ADAR regulates adipogenic miRNA targets with aging: The goal of this aim is to determine if ADARs regulate the mRNA targets of adipogenic miRNA (miR-143), adipogenic/osteogenic miRNA (miR-204) and osteogenic miRNA (miR-22). AIM 3: To demonstrate that modulation of ADAR levels in aging pre-adipocytes will improve adipocyte function. The goal of this aim is to demonstrate the role of ADAR-mediated RNA editing pathways in pre-adipocyte dysfunction with aging by using gain or loss of function approaches for modulating ADAR levels. Our proposed studies are novel and innovative and will, for the first time, explore the role of RNA editing in adipose biology and its relation to metabolic dysfunction and identify novel therapeutic targets. These studies will provide excellent research experience and opportunity for Marshall University undergraduates in the biomedical field.

 描述（由申请人提供）：衰老是一个复杂的过程，涉及细胞损伤的持续积累。预防这些损害的干预措施将改善与衰老相关的病症。脂肪功能障碍随着年龄的增长而增加，这会极大地改变脂肪量、重新分布和功能，导致代谢失衡并增加心脏代谢疾病的风险。脂肪细胞的持续更新以及新的前脂肪细胞（或脂肪干细胞）和脂肪细胞的招募对于维持脂肪质量和功能至关重要。我们最近的研究表明，由于脂肪生成 microRNA (miRNA) 的失调，前脂肪细胞随着年龄的增长而无法分化为脂肪细胞，从而导致脂肪库中出现年龄依赖性功能障碍。前脂肪细胞分化受到遗传和表观遗传机制的调节。了解这一现象很重要，因为它将有助于（i）更好地了解衰老表型与脂肪功能障碍之间的关系，以及（ii）确定治疗或预防与衰老相关的心脏代谢疾病的目标。作用于 RNA 的腺苷脱氨酶 (ADAR) 家族酶是转录后调节的关键，并且通过 RNA 编辑对 RNA 和蛋白质多样性至关重要。 ADAR 的丧失导致美国百岁老人的死亡率增加，并增加了患与年龄相关的神经系统疾病（例如痴呆症和某些癌症）的风险。 ADAR 的缺失还会导致肥胖和胰岛素抵抗增加。 ADAR 目前被探索作为某些神经系统疾病和癌症的良好治疗靶点。我们假设随着年龄的增长 ADAR 的丧失在观察到的年龄介导的脂肪功能障碍中发挥了作用。我们将通过提出三个目标来检验这一假设。我们的研究将使用从年轻 Fischer 344 x Brown 挪威杂交大鼠（6 个月）的内脏脂肪中分离出的前脂肪细胞，与老年 FBN 大鼠（​​14 个月、24 个月、30 个月）进行比较。这些老鼠与人类相似，随着年龄的增长会出现肥胖和胰岛素抵抗。目标 1：证明 ADAR 在衰老过程中 miRNA 调节脂肪功能中的作用。该目的的目的是研究 ADAR 的表达和活性是否随着年龄的增长而改变，以及它在脂肪生成 miRNA 和脂肪功能损伤中发挥的作用。目标 2：证明 ADAR 随着衰老调节脂肪形成 miRNA 靶标：该目标是确定 ADAR 是否调节脂肪形成 miRNA (miR-143)、脂肪形成/成骨 miRNA (miR-204) 和成骨 miRNA (miR-22) 的 mRNA 靶标。目标 3：证明调节衰老前脂肪细胞中的 ADAR 水平将改善脂肪细胞功能。该目的的目的是通过使用功能获得或丧失的方法来调节 ADAR 水平，证明 ADAR 介导的 RNA 编辑途径在衰老过程中前脂肪细胞功能障碍中的作用。我们提出的研究新颖且具有创新性，将首次探索 RNA 编辑在脂肪生物学中的作用及其与代谢功能障碍的关系，并确定新的治疗靶点。这些研究将为马歇尔大学生物医学领域的本科生提供优秀的研究经验和机会。