Genetics regulators of vascular smooth muscle thermogenic differentiation

血管平滑肌生热分化的遗传调节因子(M.Lynes，项目负责人) 肥胖和代谢综合征是主要的公共健康负担，当脂肪量增加时会发生，导致 脂肪组织功能障碍。肥胖与生热棕色的存在呈负相关。 脂肪组织(BAT)，可在暴露在低温下的人类和小鼠身上检测到。少校 脂肪组织中的细胞类型是脂肪细胞，除了白色脂肪细胞外，表达解偶联的细胞 蛋白1(Ucp1)是一种棕色、米色或可聚集的生热脂肪细胞。脂肪细胞可以起源于 两个不同的谱系；源自表达血小板的间充质前脂肪细胞的典型谱系 衍生生长因子受体α(PDGFRA)，或新发现的血管平滑肌(VSM)谱系 被冷攻击招募，其特征是瞬时受体电势阳离子的表达 通道子家族V成员1(TRPV1)。重要的是，来自TRPV1+VSM谱系的细胞可以表达更多 UCP1高于其他脂肪细胞，支持它们是一种不同的细胞类型的前提。我们建议写一部小说 假设TRPV1+VSM来源的脂肪细胞是一种独特的脂肪细胞类型，可以调节整个身体 新陈代谢。为了验证这一假设，我们的目标是：1)抑制TRPV1+VSM来源的脂肪细胞的脂肪生成，并 确定对系统代谢的影响；以及2)利用独特的蛋白质组签名TRPV1+VSM 以鉴定脂肪细胞的功能网络，以供进一步研究。我们将利用TRPV1谱系追踪 小鼠模型追踪TRPV1+VSM细胞对生热脂肪细胞的贡献。在第一个目标中，我们将 利用CRISPR介导的基因编辑在TRPV1+细胞中特异性地阻断Ppar信号，并量化 TRPV1+VSM系脂肪细胞的频率及其对血糖和甘油三酯的影响 新陈代谢。在第二个目标中，我们将采取一种公正的方法来鉴定来自 并将其与典型的PDGFRA脂肪细胞系的细胞进行比较。这些蛋白质是 然后可以使用我们的TRPV1谱系追踪模型编辑已识别的基因，以确定它们对脂肪生成的影响 和全身新陈代谢。该项目将得到Cobre生理学核心(细胞)的大力支持 生物能量学)，组织病理学和显微镜核心(用于组织处理、染色、分析和共聚焦 以及蛋白质组学和脂质组学核心(脂质和蛋白质图谱)。这一创新项目是由 由一位新的初级调查员Matthew Lynes博士主持，他将在 脂肪组织发育领域(Patrick Seale PhD)、生热脂肪(Shingo Kajimura PhD)和小鼠 遗传学(约瑟夫·纳多博士)。TRPV1+VSM来源的脂肪细胞在系统性红斑狼疮中的作用 新陈代谢及其独特的蛋白质特征可能为治疗肥胖症提供新的靶点和策略 和代谢综合症。

Genetic regulators of vascular smooth muscle thermogenic differentiation (M. Lynes, Project Lead) Obesity and metabolic syndrome are major public health burdens and occur when fat mass increases, leading to dysfunction in adipose tissue. Obesity is negatively associated with the presence of thermogenic brown adipose tissue (BAT), which can be detected in humans and mice exposed to cold temperatures. The major cell type in adipose tissue is the adipocyte, and in addition to white adipocytes, cells that express Uncoupling protein 1 (Ucp1) are termed brown, beige, or recruitable thermogenic adipocytes. Adipocytes can arise from two distinct lineages; the canonical lineage derived from mesenchymal preadipocytes that express platelet derived growth factor receptor alpha (Pdgfra), or a newly identified vascular smooth muscle (VSM) lineage that are recruited by cold challenge and are characterized by the expression of Transient receptor potential cation channel subfamily V member 1 (Trpv1). Importantly, cells from the Trpv1+ VSM lineage can express more UCP1 than other adipocytes, supporting the premise that they are a distinct cell type. We propose the novel hypothesis that Trpv1+ VSM derived adipocytes are a unique type of fat cell that can regulate whole body metabolism. To test this hypothesis, we aim to: 1) inhibit adipogenesis of Trpv1+ VSM derived adipocytes and determine the impact on systemic metabolism; and 2) utilize the unique proteomic signature Trpv1+ VSM derived adipocytes to identify functional networks for further study. We will utilize a Trpv1 lineage tracing mouse model to track the contribution of Trpv1+ VSM cells to thermogenic adipocytes. In the first aim, we will block Ppara signaling using CRISPR-mediated gene editing specifically in Trpv1+ cells and quantify the frequency of adipocytes from the Trpv1+ VSM lineage as well as the effect on glucose and triglyceride metabolism. In the second aim, we will take an unbiased approach to identify the proteome of adipocytes from the Trpv1+ lineage and compare it to cells from the canonical Pdgfra lineage of adipocytes. Proteins that are identified can then be edited using our Trpv1 lineage tracing model to determine their impact on adipogenesis and systemic metabolism. This project will be strongly supported by the COBRE Physiology Core (for cellular bioenergetics), the Histopathology and Microscopy Core (for tissue processing, staining, analysis, and confocal microscopy), and the Proteomics and Lipidomics Core (lipid and protein profiling). This innovative project is led by a new junior investigator, Dr. Matthew Lynes, who will be supported by outstanding expert mentors in the fields of adipose tissue development (Patrick Seale PhD), thermogenic fat (Shingo Kajimura PhD) and mouse genetics (Joseph Nadeau PhD). Determining the role of Trpv1+ VSM derived adipocytes in systemic metabolism as well as their unique protein signature could provide new targets and strategies to treat obesity and metabolic syndrome.