Coupling novel non-invasive imaging methods and new gene therapies to detect and treat type 2 diabetes

将新型非侵入性成像方法与新基因疗法相结合来检测和治疗 2 型糖尿病

• 批准号: 2609333
• 金额: --
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2609333
• 关键词: Coupling; novel; non; invasive; imaging

Appropriately functioning adipose tissue is essential for human health. This is most dramatically illustrated by lipodystrophy syndromes, in which the inability to develop or maintain adipose tissue properly often leads to severe metabolic disease including fatty liver and diabetes. Obese individuals also suffer relative adipose insufficiency because their adipocytes become overfilled and so unable to store further nutrients appropriately. As in lipodystrophy, lipids then spill over into other tissues, especially the liver, causing insulin resistance and diabetes. Thus, the mechanisms underpinning the negative metabolic consequences of obesity and lipodystrophy overlap significantly. Lipodystrophy is a devastating and under-reported condition. The only currently effective therapy is the hormone leptin, normally secreted by adipose tissue and reduced or absent in lipodystrophy patients. Leptin acts to suppress hunger but also has beneficial effects in the liver of patients, reducing fatty liver and improving their diabetes. Leptin may also have beneficial effects in a subset of overweight individuals with fatty liver and diabetes. However, leptin treatment requires painful daily injections and the high cost means it is rarely available to patients. Lipodystrophy patients, and obese, diabetic individuals, can also have low levels of another hormone secreted by adipose called adiponectin. Adiponectin improves insulin sensitivity via multiple mechanisms. However, the effects of adiponectin replacement in lipodystrophy have not been examined.In this project we will exploit our recently developed ability to use adeno-associated virus (AAV) driven expression of proteins as gene therapy in a pre-clinical model of lipodystrophy. We will use AAV to deliver leptin and/or adiponectin to restore levels of these hormones. We will then examine how these treatments affect insulin sensitivity and other metabolic health measures, in particular fatty liver disease. As part of this work we will apply a novel, cutting-edge non-invasive imaging method called Fast Field-Cycling imaging (FFC imaging) to compare fatty liver disease in obesity and lipodystrophy. We will also define how fatty liver disease is affected by AAV gene therapy in our preclinical model of lipodystrophy. FFC techniques have shown excellent capabilities from human pilot studies on the characterisation of fatty tissues and fibrosis, being able to differentiate different types of adipose tissue and to detect the different stages of fibrosis in non-alcoholic fatty liver disease. This method will allow us to assess treatment effects and to facilitate translation to human studies in future studies.Overall this project combines the study of metabolic health in rare and common disease with preclinical analysis of new potential gene therapy approaches as well as cutting edge medical physics methods. Together this will allow us to define new ways to understand, diagnose and treat fatty liver, a signature feature of metabolic disease that underpins the development of type 2 diabetes.

适当的脂肪组织功能对人体健康至关重要。脂肪营养不良综合症最引人注目地说明了这一点，其中无法正常发育或维持脂肪组织通常会导致严重的代谢疾病，包括脂肪肝和糖尿病。肥胖的个体也遭受相对脂肪不足，因为他们的脂肪细胞变得过度填充，因此无法适当地储存更多的营养。在脂肪代谢障碍中，脂质然后溢出到其他组织中，特别是肝脏，引起胰岛素抵抗和糖尿病。因此，肥胖和脂肪代谢障碍的负面代谢后果的基础机制明显重叠。脂肪代谢障碍是一种毁灭性的和报告不足的条件。目前唯一有效的治疗是激素瘦素，通常由脂肪组织分泌，在脂肪营养不良患者中减少或不存在。瘦素的作用是抑制饥饿，但也对患者的肝脏有有益的影响，减少脂肪肝和改善糖尿病。瘦素也可能对脂肪肝和糖尿病的超重个体亚组有有益的影响。然而，瘦素治疗需要每天痛苦的注射，高昂的费用意味着患者很少能获得。脂肪代谢障碍患者和肥胖、糖尿病个体也可以具有低水平的另一种由脂肪分泌的称为脂联素的激素。脂联素通过多种机制改善胰岛素敏感性。然而，脂联素替代在脂肪代谢障碍中的作用还没有被研究。在这个项目中，我们将利用我们最近开发的能力，使用腺相关病毒（AAV）驱动的蛋白质表达作为基因治疗在脂肪代谢障碍的临床前模型。我们将使用AAV来递送瘦素和/或脂联素以恢复这些激素的水平。然后，我们将研究这些治疗如何影响胰岛素敏感性和其他代谢健康指标，特别是脂肪肝。作为这项工作的一部分，我们将应用一种新的，尖端的非侵入性成像方法，称为快速场循环成像（FFC成像），以比较肥胖和脂肪代谢障碍中的脂肪肝疾病。我们还将定义脂肪肝疾病是如何在我们的脂肪代谢障碍的临床前模型中受到AAV基因治疗的影响。FFC技术在对脂肪组织和纤维化的表征进行的人类试点研究中显示出出色的能力，能够区分不同类型的脂肪组织并检测非酒精性脂肪肝疾病中纤维化的不同阶段。这种方法将使我们能够评估治疗效果，并促进在未来的研究中转化为人类研究。总体而言，该项目将罕见和常见疾病的代谢健康研究与新的潜在基因治疗方法的临床前分析以及尖端医学物理方法相结合。总之，这将使我们能够定义新的方法来理解，诊断和治疗脂肪肝，这是代谢疾病的一个标志性特征，是2型糖尿病发展的基础。