Role of Jagged1 in Adipogenesis and Adipocyte Function

描述（由申请人提供）：脊椎动物的白色脂肪组织（WAT）发育是通过组织中脂肪细胞的大小和数量的增加而发生的。包括NIDDM （II型糖尿病）在内的几种病理状况的发生与肥胖和脂肪萎缩密切相关。脂肪细胞起源于多能间充质干细胞，在内分泌和其他外部信号的作用下发生分化。虽然已经确定了调节脂肪细胞分化途径最后阶段的关键转录激活因子，但最初导致未分化干细胞采用脂肪细胞命运的分子机制尚未得到很好的阐明。此外，对维持成熟脂肪细胞功能表型的细胞过程知之甚少。更好地了解控制脂肪细胞生长和功能的分子机制可能有助于开发用于预防和治疗肥胖及相关疾病的治疗剂。Notch受体及其配体产生的信号可能是控制脂肪细胞分化和功能的一种可能机制，因为Notch信号在成熟组织中调节细胞分化和稳态。Notch受体和配体在脂肪形成细胞的整个分化过程中表达，并在成熟细胞中持续存在，但对它们如何调节脂肪细胞的生命周期和功能知之甚少。本提案的目的是通过体外和体内的功能增益和功能丧失模型，专门研究Notch配体Jagged 1在脂肪形成和成熟脂肪细胞中的需求。为了实现这一目标，提出了以下具体目标：具体目标1：描述Jagged1在脂肪从间充质干细胞/祖细胞到成熟的特化细胞的形成过程中的功能作用；特异性目的2：确定Jagged 1在维持脂肪组织中成熟功能性脂肪细胞表型中的作用。

DESCRIPTION (provided by applicant): White adipose tissue (WAT) development in vertebrates occurs through an increase in both the size and number of adipocytes residing in the tissue. The occurrence of several pathological conditions including NIDDM (Type II diabetes) is strongly correlated with both obesity and lipoatrophy. The adipocyte arises from a pluripotent mesenchymal stem cell that undergoes differentiation in response to endocrine and other external signals. While key transcriptional activators that regulate the final stages in the adipocyte differentiation pathway have been identified, the molecular mechanisms that initially cause an undifferentiated stem cell to adopt the adipocyte cell fate are not well elucidated. In addition, little is known about the cellular processes that maintain the functional phenotype of the mature adipocyte. Better understanding the molecular mechanisms that govern the growth and function of adipocytes may aid in the development of therapeutic agents used for the prevention and treatment of obesity and related diseases. Signals generate by the Notch receptors and their ligands may be one possible mechanism governing adipocyte differentiation and function as Notch signaling regulates both cell differentiation and homeostasis in mature tissues. The Notch receptors and ligands are expressed in adipogenic cells throughout differentiation and persists in the mature cell, yet little is known about how they regulate the adipocyte life cycle and function. The objective of this proposal is to specifically study the requirement for the Notch ligand Jagged 1 in adipogenesis and in the mature adipocyte through the use of gain- and loss-of-function models both in vitro and in vivo. To meet this objective, the following specific aims are proposed: Specific Aim 1: To delineate the functional role of Jagged1 during adipogenesis from a mesenchymal stem cell/ progenitor to a mature, specialized cell; Specific Aim 2: To determine the role of Jagged 1 in maintaining the phenotype of a mature functional adipocyte within adipose tissue.