Pdgfrβ, a mediator of the adipose lineage

项目摘要 我们的总体研究目标是了解控制脂肪的细胞和分子机制。 血统和了解这些机制如何在代谢反应中变得功能失调 疾病。肥胖的全球流行和继发性的负面健康后果，如 2糖尿病和心血管疾病是一个重大的公共卫生问题。因此，有一个紧急的 需要更好地了解控制脂肪细胞形成的机制和分子 白色脂肪组织的扩张(Wat)。Wat是高度可塑性的，可以在 对各种动态平衡信号、药剂和饮食刺激的反应。实现这一目标的唯一途径 扩张是通过形成新的脂肪细胞。新生脂肪细胞起源于血管周围 脂肪细胞前体细胞(APC)，在解剖学和遗传学上似乎类似于壁画的一个子集 细胞(平滑肌细胞)。然而，在WAT器官发生过程中，一个明显的和谱系分离的APC 形成组织的图案和形式。这些发现导致了两种不同的APC的概念，即发育 而且是成年人。在K01获奖期间，我们发现脂肪谱系特异性破坏血小板 衍生生长因子受体β信号转导干扰成体β-NICE相互作用 并使这些APC不能成脂。然而，目前还不清楚pdgfrβ是否介导了 成年APC血统规范和Wat生态位归宿。因此，我们的研究目标是了解 形成WAT的APC和维持WAT的APC之间的细胞和分子差异 成人的组织。为了回答这一目标，我们将使用针对不同APC的独特遗传模型 继续探讨PDGFRβ在成人aPC谱系中的作用。我们在这里的初步数据 提示PDGFRβ对于成人脂肪谱系的确定和确定具有重要意义。为 例如，当PDGFRβ在成人APC群体中被缺失时，它们不再是成脂细胞，并且 在解剖学和遗传学上与巨噬细胞相似。这些数据支持了我们的假设，即PDGFRβ是一种 成人脂肪谱系决定因素。我们建议测试PDGFRβ的遗传需求和 成人APC在维护和扩大WAT(目标1)。此外，我们还建议探索分子 β调控脂肪谱系和APC形成现象的机制(S) 脂肪组织驻留巨噬细胞(目标2)。这些研究的成功完成将提供 成人APC谱系如何被指定和确定导致健康脂肪组织的新进展 形成和扩张。此外，这些对控制脂肪谱系的机制的见解 生物学可能导致帮助对抗肥胖症和2型糖尿病的策略。

Project Summary Our overall research goal is to understand the cellular and molecular mechanisms governing the adipose lineage and to understand how these mechanisms become dysfunctional in response to metabolic diseases. The worldwide epidemic of obesity and secondary negative health consequences such as type 2 diabetes and cardiovascular disease are a significant public health problem. Thus, there is an urgent need to better understand the mechanisms and molecules that control the formation of adipocytes and the expansion of white adipose tissue (WAT). WAT is highly plastic and can expand and shrink in response to various homeostatic cues, pharmacologic agents, and dietary stimuli. One way that WAT expands is through the formation of new adipocytes. New adipocytes emanate from a perivascular adipocyte precursor cell (APC) which appears to anatomically and genetically resemble a subset of mural cells (smooth muscle cells). However, during WAT organogenesis a distinct and lineage separate APC patterns and forms the tissues. These findings have led to the notion of two distinct APCs, developmental and adult. During the K01 award period, we discovered that adipose lineage specific disruption of platelet derived growth factor receptor beta (Pdgfrβ) signaling interferes with adult APC-niche interaction and communication and renders these APCs non-adipogenic. However, it was unclear if Pdgfrβ mediated adult APC lineage specification and WAT niche homing. Thus, our research objective is to understand the cellular and molecular differences between the APCs that develop WAT versus those that maintain the adult tissue. To answer this objective, we will use unique genetic models that target different APC populations to continue to probe the role of Pdgfrβ in the adult APC lineage. Our preliminary data herein suggest that Pdgfrβ is critical for the specification and determination of the adult adipose lineage. For instance, when Pdgfrβ is deleted within the adult APC population, they are no longer adipogenic and anatomically and genetically resemble macrophages. These data frame our hypothesis that Pdgfrβ is an adult adipose lineage determination factor. We propose to test the genetic requirement of Pdgfrβ and adult APCs in maintaining and expanding WAT (aim 1). Further we propose to explore the molecular mechanism(s) by which Pdgfrβ controls the adipose lineage and phenomenon by which APCs can form adipose tissue resident macrophages (aim 2). The successful completion of these studies will provide new inroads into how the adult APC lineage is specified and determined leading to healthy adipose tissue formation and expansion. Moreover, these insights into the mechanisms governing adipose lineage biology may lead to strategies to assist in counteracting obesity and type 2 diabetes.