Physiological Role of Dedifferentiating Dermal Adipose Tissue

真皮脂肪组织去分化的生理作用

基本信息

批准号：
10348609
负责人：
PHILIPP E SCHERER
金额：
$ 51.82万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348609
关键词：
Address Adipocytes Adipose tissue Agonist Apoptosis Attenuated Bleomycin Cells Characteristics Collagen Cre lox recombination system Deposition Dermal Dermis Ensure Extracellular Matrix Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Genetic Genetic Models Heterogeneity High Fat Diet Immune system Inflammation Label Laboratories Leptin Light Link Lipids Lipolysis Metabolic Metabolism Mind Modeling Mus Mutation Myofibroblast Nature PPAR gamma Pathogenesis Pathologic Physiological Population Process Production Reporting Role Skin System Thick Time Tissues Topical application Translating Up-Regulation adipocyte differentiation adipokines adiponectin autocrine base cell type dermal exposure design driving force feeding genetic approach genetic manipulation in vivo insight loss of function mouse model novel overexpression paracrine precursor cell prevent promoter response rosiglitazone single cell sequencing skin fibrosis skin lesion transdifferentiation

项目摘要

Abstract Physiological Role of De-differentiating Dermal Adipose Tissue Adipose tissue fibrosis is an integral component of dysfunctional fat tissue. This fibrosis exerts detrimental effects on local metabolic responses within adipose tissue, in addition to initiating maladaptive systemic responses. The exact cause(s) of fibrosis in adipose tissue are still a matter of debate and as such, are not well defined. Here, we aim to focus on “dermal adipose tissue fibrosis”, primarily due to its 1) ease of accessibility, 2) our new genetic mouse models that we generated to specifically examine dermal adipose tissue dysfunction and, 3) our initial observation that identified extensive dermal adipocyte differentiation and de-differentiation. We believe that the latter processes are a key aspect of the pathological road to adipose tissue fibrosis. Dermal adipose tissue is skin-associated fat located directly under the reticular dermis. Compared to other well-defined fat pads, dermal adipose tissue displays a high degree of plasticity. Under a variety of physiological conditions, dermal adipose tissue has the capacity to either rapidly and locally expand, or reduce its volume. Our in vivo preliminary studies showed that dermal adipose tissue is negatively associated with collagen production in skin fibroblasts. Importantly, more recent studies in our laboratory identified that the highly dynamic nature of dermal adipocytes allows them to 1) undergo de-differentiation into pre-adipocytes or, 2) convert into alpha-SMA-positive myofibroblasts (when examined in a bleomycin-induced fibrosis model). Here, we propose to examine the following hypothesis: that the adipocyte itself is the major player in preventing adipose tissue fibrosis in response to a metabolic challenge of high fat diet feeding, or bleomycin induction. We will address our hypothesis in three Specific Aims: I) We will retain fat cells in a fully differentiated state, by either ectopically exposing dermal adipocytes to PPARgamma agonists. In parallel, we aim to genetically overexpress PPARgamma then assess the impact on the fibrotic response. In addition to this, we will examine the impact of a complete elimination of adipocytes upon the local fibrotic response in the skin. II) Through lineage tracing, we aim to genetically label and track mature adipocytes as they de-differentiate into pre-adipocytes. Some of these pre- adipocytes can convert to myofibroblasts. We have developed a genetic approach to selectively eliminate myofibroblasts that originate from mature adipocytes. This will allow us, for the first time, to examine the functional relevance of these adipocyte-derived myofibroblasts towards the fibrotic response in adipose tissue. III) With a newly developed “Split Cre” system, we take advantage of a dual promoter system that ensures expression uniquely in the dermal adipocyte. We will manipulate leptin and adiponectin levels locally, then address the impact of local adipokine action in the microenvironment of the dermal adipose tissue on the fibrotic response. While we focus on dermal adipose tissue, results from the proposed studies will also have a profound impact on the understanding of the fibrotic response in other fat depots.

抽象的真皮脂肪组织去分化的生理作用脂肪组织纤维化是功能失调的脂肪组织的一个组成部分，这种纤维化会产生疼痛。除了引发全身适应不良外，还对脂肪组织内的局部代谢反应产生影响脂肪组织纤维化的确切原因仍然存在争议，因此也没有争议。在这里，我们的目标是关注“真皮脂肪组织纤维化”，主要是因为它 1) 容易发生。可及性，2）我们生成的新基因小鼠模型专门用于检查真皮脂肪组织功能障碍，3）我们的初步观察发现了广泛的真皮脂肪细胞我们认为，后一过程是分化的关键方面。脂肪组织纤维化的病理途径真皮脂肪组织是直接位于皮肤的脂肪。与其他轮廓明确的脂肪垫相比，真皮脂肪组织表现出较高的脂肪含量。在各种生理条件下，真皮脂肪组织都具有一定程度的可塑性。我们的体内初步研究表明，真皮会迅速局部扩张，或缩小其体积。更重要的是，脂肪组织与皮肤成纤维细胞中胶原蛋白的产生呈负相关。我们实验室最近的研究发现，真皮脂肪细胞的高度动态特性使它们能够 1) 去分化为前脂肪细胞，或 2) 转化为 α-SMA 阳性肌成纤维细胞（在博来霉素诱导的纤维化模型中进行检查时）在这里，我们建议检查以下内容。假设：脂肪细胞本身是预防脂肪组织纤维化的主要因素应对高脂肪饮食喂养或博莱霉素诱导的代谢挑战我们将解决我们的问题。三个具体目标的假设：I）我们将通过异位或异位将脂肪细胞保持在完全分化的状态与此同时，我们的目标是在基因上过度表达 PPARgamma。评估对纤维化反应的影响除此之外，我们还将检查完整的影响。 II) 通过谱系追踪，我们的目标是消除皮肤局部纤维化反应中的脂肪细胞。当成熟脂肪细胞去分化为前脂肪细胞时，对它们进行基因标记和跟踪。我们开发了一种遗传方法来选择性消除脂肪细胞。源自成熟脂肪细胞的肌成纤维细胞这将使我们第一次能够检查肌成纤维细胞。这些脂肪细胞衍生的肌成纤维细胞与脂肪组织纤维化反应的功能相关性。 III) 通过新开发的“Split Cre”系统，我们利用双启动子系统，确保我们将在真皮脂肪细胞中独特地表达瘦素和脂联素水平，然后解决真皮脂肪组织微环境中局部脂肪因子作用对虽然我们关注真皮脂肪组织，但拟议研究的结果也将是。对理解其他脂肪库的纤维化反应具有深远的影响。