Brown Adipose Tissue Vasculature Probes for Non-Invasive Imaging

用于非侵入性成像的棕色脂肪组织脉管系统探头

• 批准号: 8043433
• 负责人: Mikhail G Kolonin
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043433
• 关键词: Adipocytes; Adipose tissue; Adult; Aging; Animal Model; Animals; Binding; Biodistribution; Bioinformatics; Biological Markers; Biology; Biopsy; Blood Vessels; Brown Fat; Cell Surface Receptors; Coupled; Detection; Development; Disease; Dyes; Equilibrium; Future; Genetic; Glucose; Goals; Heterogeneity; Homing; Human; Hyperplasia; Hypertrophy; Image; Individual; Label; Lead; Life; Ligands; Link; Mammals; Maps; Measures; Medical; Metabolic; Methods; Molecular; Mus; Muscle; Nervous system structure; Obesity; Organ; Outcome; Patients; Peptide Library; Peptides; Phage Display; Positron-Emission Tomography; Property; Residual state; Rodent; Signal Transduction; Specificity; Stimulus; Stress; System; Testing; Thermogenesis; Tissues; Translating; Validation; X-Ray Computed Tomography; base; combinatorial; design; drug discovery; high throughput screening; improved; in vivo; mouse model; novel strategies; obesity management; obesity treatment; overexpression; prospective; protective effect; receptor; research study; response; subcutaneous; tool; transdifferentiation; vector

DESCRIPTION (provided by applicant): Studies in animal models indicate that brown adipose tissue (BAT) has a protective effect against the pathological consequences of obesity, a medical condition complicating life-threatening diseases. The unique function of brown adipocytes in energy dissipation through adaptive thermogenesis opposes the action of white adipocytes, hypertrophy and hyperplasia of which are responsible for obesity. In addition to this explanation for the beneficial effect of BAT, transdifferentiation of white adipocytes into brown adipocytes has been shown to take place in response to cold or other symphatetic nervous system stimuli in rodents. Recently, functional BAT in adult humans has been detected by positron emission tomography (PET), outlining new avenues in treatment of obesity and the associated disorders. Most adults appear to have BAT revealed by biopsy, however it is often metabolically inactive in obese and aging individuals and is undetectable by PET. Therefore, distribution of BAT in humans remains incompletely characterized, and the establishment of approaches for reliable localization and quantification of BAT depots is necessary. The goal of this project is to establish an approach to assess BAT depots irrespective of their metabolic activity. We propose to identify probes targeting markers differentially expressed in adult BAT vasculature and to use them for non-invasive localization of BAT. First, we will use the mouse model to isolate ligands (small peptides) that bind to receptors specifically expressed in the BAT vasculature. BAT-homing ligands will be isolated by integrating a screen of a phage-displayed combinatorial peptide library in vivo with the bioinformatics platform established by our group. Next, we will use these BAT-homing peptides to test and optimize non-invasive imaging of BAT with a peptide-conjugated near-infrared (NIR) dye in the mouse model. BAT localization of systemically administered peptide conjugates will be validated via conventional PET, computed tomography, and tissue immunostaining for BAT markers. Genetic background-specific modulation of BAT amount and metabolic activity in these experiments will establish the sensitivity of our approach and the properties of BAT depots compatible with detection. This non-invasive BAT imaging through ligand-directed imaging agent delivery will be advantageous because it is not based on tissue metabolic activity. Eventually, BAT probes isolated in this study could be used for identification of the targeted receptors and their validation as BAT biomarkers. Subsequently, improved vectors could be designed to target these biomarkers in BAT. Because vascular ligand/receptor systems uncovered through combinatorial peptide library screens tend to be conserved among mammals, we predict that peptides isolated in mice will cross-react with human vascular BAT receptors that are likely to also be differentially expressed. The long-term goal of this study is to translate the tools developed here for designing a method for quantifying BAT depots in humans that will be robust, affordable and potentially highly specific. PUBLIC HEALTH RELEVANCE: The novel approach to non-invasive imaging of BAT developed here will have significant advantages to currently practiced BAT detection with PET: it will not depend on BAT metabolic activity, is likely to produce less non-specific false positive signals in other metabolically active organs, and will be cheaper and more generally available. Based on the BAT-targeting probes generated in our study, new pharmacological approaches to convert white adipose tissue to BAT could be developed as a prospective strategy to treat obesity.

描述（由申请人提供）：动物模型的研究表明，棕色脂肪组织（BAT）对肥胖症的病理后果具有保护作用，这种医疗状况使危及生命的疾病复杂化。棕色脂肪细胞在能量耗散中的独特功能通过适应性热发生在能量耗散中反对白色脂肪细胞，肥大和增生的作用，其肥胖是造成肥胖的。除了对蝙蝠的有益作用的解释外，还显示将白脂肪细胞转变为棕色脂肪细胞，以响应啮齿动物的冷或其他同型神经系统刺激。最近，通过正电子发射断层扫描（PET）检测到成年人的功能性蝙蝠，概述了肥胖症和相关疾病的新途径。大多数成年人似乎都被活检揭示出来，但是在肥胖和老龄化的个体中，它通常在代谢上不活跃，而宠物无法检测到。因此，人类中蝙蝠的分布仍然没有完全表征，并且必须建立可靠定位和量化蝙蝠库的方法。该项目的目的是建立一种评估蝙蝠库的方法，无论其代谢活动如何。我们建议确定针对成年BAT脉管系统差异表达的标记物的探针，并将其用于非侵入性蝙蝠定位。首先，我们将使用小鼠模型分离与在蝙蝠脉管系统中特异性表达的受体结合的配体（小肽）。通过将体内的噬菌体播放组合肽库与我们小组建立的生物信息学平台集成一个噬菌体播放的组合肽库的屏幕，将隔离蝙蝠。接下来，我们将使用这些蝙蝠携带的肽在小鼠模型中使用肽偶联的近红外（NIR）染料测试和优化BAT的非侵入性成像。蝙蝠的定位将通过常规PET，计算机断层扫描和蝙蝠标记的组织免疫染色来验证。在这些实验中，蝙蝠量和代谢活性的遗传背景特异性调节将确定我们方法的敏感性以及与检测兼容的蝙蝠库的性质。这种通过配体导向剂输送的非侵入性蝙蝠成像将是有利的，因为它不是基于组织代谢活性。最终，本研究中分离出的BAT探针可用于识别靶向受体及其作为BAT生物标志物的验证。随后，可以设计改进的矢量以瞄准这些生物标志物。由于通过组合肽库筛查发现的血管配体/受体系统往往是在哺乳动物中保守的，因此我们预测，在小鼠中分离的肽将与可能也有差异表达的人血管蝙蝠受体进行反应。这项研究的长期目标是翻译此处开发的工具，该工具用于设计一种量化人类中蝙蝠库的方法，该方法将是强大，负担得起且潜在的高度特异性的。 公共卫生相关性：此处开发的蝙蝠的非侵入性成像的新型方法将具有当前使用PET检测的BAT检测的显着优势：它不会依赖于BAT代谢活动，可能会在其他代谢性活性器官中产生较少的非特异性假信号，并且更便宜，并且更便宜且普遍可用。基于我们研究中产生的蝙蝠靶向探针，可以开发出新的药理学方法将白脂肪组织转化为BAT，作为治疗肥胖症的前瞻性策略。