Pdgfrβ, a mediator of the adipose lineage

Pdgfrβ，脂肪谱系的调节者

• 批准号: 9807355
• 负责人: Daniel Carl Berry
• 金额: $ 11.78万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807355
• 关键词: Adipocytes; Adipose tissue; Adult; Anatomy; Biology; Blood Glucose; Blood Vessels; Cardiovascular Diseases; Cell Lineage; Cells; Cellular biology; Clinical; Communication; Comorbidity; Cues; Data; Development; Diet; Embryo; Epidemic; Fatty acid glycerol esters; Future; Genes; Genetic; Genetic Models; Goals; Health; Homeostasis; Homing; Influentials; Investigation; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Metabolic; Metabolic Diseases; Metabolic dysfunction; Molecular; Molecular Probes; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Organogenesis; Overweight; Pathway interactions; Pattern; Pharmacology; Phenotype; Platelet-Derived Growth Factor beta Receptor; Population; Positioning Attribute; Process; Property; Public Health; Research; Residencies; Risk; Role; Signal Transduction; Smooth Muscle Myocytes; Specific qualifier value; Stimulus; Testing; Therapeutic; Tissue Expansion; Tissues; blastomere structure; design; in vivo; insight; macrophage; novel; obesogenic; postnatal; precursor cell; residence; response

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.

项目摘要 我们的总体研究目标是了解依控制脂肪的细胞和分子机制 血统并了解这些机制如何响应代谢功能失调 疾病。肥胖症和继发性健康后果（例如类型）的全球流行病 2种糖尿病和心血管疾病是一个重大的公共卫生问题。那是紧急的 需要更好地理解控制脂肪细胞形成的机制和分子 白色脂肪组织（WAT）的膨胀。 WAT是高度塑料的，可以扩展和收缩 对各种稳态提示，药物和饮食刺激的反应。一种方法 扩展是通过形成新的脂肪细胞。新的脂肪细胞源自周围的 脂肪细胞前体细胞（APC），在解剖学和一般看起来像壁画的子集 细胞（平滑肌细胞）。但是，在WAT器官发生过程中 模式并形成组织。这些发现导致了两个不同的APC的概念 和成人。在K01奖励期间，我们发现脂肪谱系特定的血小板破坏 衍生的生长因子受体β（PDGFRβ）信号传导干扰成人APC-niche相互作用和 交流并使这些APC非辅助。但是，尚不清楚PDGFRβ是否介导 成人APC谱系规范和wat小众归巢。那是我们的研究目标是了解 与维持的APC相比，APC之间的细胞和分子差异 成人组织。为了回答这个目标，我们将使用针对不同APC的独特遗传模型 种群继续探测PDGFRβ在成年APC谱系中的作用。我们本文的初步数据 表明PDGFRβ对于成人脂肪谱系的规范和测定至关重要。为了 实例，当PDGFRβ在成年APC种群中删除时，它们不再是脂肪性的，并且 解剖学和一般类似于巨噬细胞。这些数据框架我们的假设是PDGFRβ是 成人脂肪谱系测定因子。我们建议测试PDGFRβ和 成年APC维持和扩展WAT（AIM 1）。此外，我们建议探索分子 PDGFRβ控制脂肪谱系和APC可以形成的现象的机制 脂肪组织居民巨噬细胞（AIM 2）。这些研究的成功完成将提供 对成年APC谱系的指定并确定导致健康脂肪组织的新侵害 形成和扩展。此外，这些对管理脂肪血统机制的见解 生物学可能会导致策略协助抵消肥胖和2型糖尿病。