Biomarkers, Lineage Analysis--metabolic disease states

描述(由申请人提供)：我们的总体目标是阐明控制脂肪组织形成的机制，并确定这些过程在代谢性疾病期间是否以及如何改变。储存能量的能力，主要是以脂肪的形式，是许多高等生物体生命周期所必需的一种迷人的特性。不幸的是，脂肪积累的异常会产生包括脂肪营养不良、糖尿病和肥胖在内的病理状态，这些都是全世界发病率和死亡率的主要原因。然而，调控脂肪细胞发育和生理的基因还没有完全被了解。模式生物已被证明是基因发现、阐明基因功能和表征发育的强大工具。因此，开发模型来更全面地描述健康和不健康条件下的脂肪生物学将是一件很棒的事情。令人惊讶的是，人们对脂肪细胞的发育知之甚少。产生脂肪细胞的细胞的位置和谱系仍然未知，脂肪细胞干细胞的起源和身份也不确定。脂肪组织至少由三种不同的类型组成：棕色脂肪、白色机械脂肪和白色代谢性脂肪。脂肪细胞被放置在固定的位置，散布在全身。不同类型和储存的脂肪细胞在形态和功能上不同，具有不同的代谢特征，对健康具有至关重要的影响。然而，控制形态发生、位置和功能差异的机制和发育线索尚不清楚。为了开始了解不同的脂肪组织是如何在代谢性疾病期间形成、图案化、再生和改变的，我们正在系统地分离标记不同发育阶段和不同储存库的分子。此外，我们已经并将继续产生体内谱系示踪剂，以标记、检测和分离处于不同发育阶段的脂肪细胞和脂肪细胞前体细胞，以及从处于生理和病理生理状态的个体脂肪库中分离脂肪细胞和脂肪细胞前体细胞。这些研究可能会阐明脂肪细胞的行为，并可能允许合理设计治疗脂肪营养不良、肥胖和糖尿病的方法。目的一、开发脂肪生物标记物。目的II，追踪脂肪细胞的谱系。目的III，确定AIMS I和II产生的生物标记物和谱系示踪物在各种异常代谢状态下的表达是否以及如何改变。

DESCRIPTION (provided by applicant): Our overall objective is to elucidate the mechanisms that control formation of adipose tissues and to determine whether and how these processes are altered during metabolic diseases. The ability to store energy, primarily as fat, is a fascinating property that seems to be required for the life cycle of many higher organisms. Unfortunately, abnormalities in fat accumulation produce pathological states including lipodystrophy, diabetes, and obesity, which are major causes of morbidity and mortality throughout the world. Yet, the genes that regulate adipocyte development and physiology are not fully understood. Model organisms have proven to be powerful tools for gene discovery, for elucidating gene function, and for characterizing development. So, it would be great to exploit models to more fully characterize fat biology in healthy and unhealthy conditions. Surprisingly little is known about adipocyte development. The location and lineage of the cells that give rise to adipocytes remain unknown and the origin and identity of adipocyte stem cells are not established. Adipose tissues consist of at least three distinct types: brown fat, white mechanical fat, and white metabolic fat. Adipocytes are place in stereotypical positions dispersed throughout the body. The different types and depots of adipose cells differ morphologically and functionally, having different metabolic profiles with critical health ramifications. Yet, the mechanisms and developmental cues that control the morphogenesis, location, and functional differences are unknown. To begin to understand how diverse fat tissues are formed, patterned, regenerate, and are altered during metabolic diseases, we are systematically isolating molecules that mark different developmental stages and distinct depots. Further, we have and will continue to generate in vivo lineage tracers to mark, detect and isolate adipocytes and adipocyte progenitors at various developmental stages and from individual fat depots both in physiologic and pathophysiologic states. These studies are likely to shed light on the behavior of adipocytes and may allow for rational design of therapies for lipodystrophy, obesity, and diabetes. Aim I, to develop adipose biomarkers. Aim II, to trace the adipocyte lineage. Aim III, to determine whether and how expression of the biomarkers and lineage tracers generated in Aims I and II are altered in various abnormal metabolic states.