Developmental lineages and functions of macrophages in white adipose tissue

白色脂肪组织中巨噬细胞的发育谱系和功能

基本信息

批准号：
10449634
负责人：
Nehemiah Cox
金额：
$ 9万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2023-02-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449634
关键词：
Adipocytes Adipose tissue Advisory Committees Affect Animals Area Biology Body Weight Bone Marrow Cachexia Cell Communication Cell Differentiation process Cell Nucleus Cell Proliferation Cells Cellular biology Cessation of life Data Deposition Development Diet Disease Drosophila genus Embryo Erythro Family Fasting Fatty acid glycerol esters Flow Cytometry Genes Genetic Genetic Transcription Glass Goals Growth Factor High Fat Diet Human Hypertrophy Immune Inflammation Insulin Resistance Larva Link Lipids Lipodystrophy Macrophage Activation Malignant Neoplasms Mediator of activation protein Mentors Metabolic Metabolism Methodology Modeling Molecular Mus Myelogenous Myeloid Cells Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Organ Organoids Orthologous Gene Patients Pharmacology Phase Physiological Platelet-Derived Growth Factor Population Population Heterogeneity Process Production Publishing Regulation Research Role Science Scientist Signal Pathway Signal Transduction Testing Therapeutic Thinness Tissues United States Visit Wild Type Mouse Yolk Sac drug development expectation experimental study fat wasting in vivo lipid metabolism macrophage mouse model mutant novel paracrine progenitor sensor systemic inflammatory response therapy development tool transcriptome sequencing

项目摘要

ABSTRACT: Adipose tissue-associated disorders including obesity, lipodystrophy, and cancer-associated fat wasting collectively account for 1 in 4 deaths in the United States (1-3). Despite the devastatingly high number of deaths, therapeutic options remain limited and unsatisfactory. Landmark studies since the 1990’s have established that accumulation and activation of macrophages in adipose tissues are linked to inflammation, insulin resistance, and type 2 diabetes (4-20). However, the roles of adipose tissue macrophages outside tissue inflammation remain poorly understood. This is particularly important, as studies suggest that adipose tissue macrophages may be involved in fat development (21-23), fat storage (24), and protection against fat wasting (25). Our preliminary data published in Science (26) demonstrate that embryo-derived adipose tissue resident macrophages promote lipid storage in adipocytes via production of PDGFcc. This process is independent from inflammation and insulin resistance promoted by bone-marrow-derived macrophages. Our preliminary data in (Aim 1) suggest that macrophages are required for fat loss. Therefore, in Aim 1 I will delineate the responsible macrophage lineages (K99) and identify macrophage-dependent mechanisms (R00) that control fat mobilization/loss. In (Aim 2), I will determine the transcriptional basis for control of lipid storage by adipose tissue resident macrophages using single nucleus RNA-sequencing (K99). I expect to deduce changes in cellular circuitries and downstream signaling pathways that control fat storage. The candidate molecules identified here will be explored in the R00 phase of this research using human fat organoids and in vivo mouse models. In (Aim 3), I will use human fat organoids that contain human resident-like macrophages to confirm the role of PDGFcc in fat storage in humans (K99). I have found that human fat organoids that contain Pdgfc+ resident-like macrophages accumulate more lipids as compared to macrophage-less fat organoids. I will (R00) use these fat organoids to determine how macrophages affect lipid metabolism and identify whether macrophages act directly on adipocytes. Additionally, human organoids will be used to screen for macrophage- dependent mediators of energy storage identified in Aims 1 and 2. I will continue to be mentored by Dr Frederic Geissmann, a leader in the field of macrophage biology. The Geissmann lab is among the first to characterize the developmental lineages and functions of macrophages. I will also benefit from the expertise of my advisory committee that includes Anthony Ferrante, Chris Glass, and Olivier Elemento. Drs. Chris Glass and Olivier Elemento are highly respected scientists with expertise in analysis of macrophages and white adipose tissues by single cell methodologies. Whereas, Drs Anthony Ferrante is an expert in the areas of myeloid cell biology, metabolism, and adipose tissue function. My expectations are that this proposal combined with my expertise in drug development will not only provide a comprehensive functional view of adipose tissue macrophages but also aid in development of therapies that may control adiposity in obese, lipodystrophic, or cachectic patients.

摘要：脂肪组织相关疾病，包括肥胖、脂肪营养不良和癌症相关脂肪尽管死亡人数高得惊人，但美国四分之一的死亡人数是由消瘦造成的（1-3）。自 20 世纪 90 年代以来，治疗选择仍然有限且不令人满意。确定脂肪组织中巨噬细胞的积累和激活与炎症有关，胰岛素抵抗和 2 型糖尿病 (4-20) 然而，脂肪组织巨噬细胞在组织外的作用。这一点尤其重要，因为研究表明脂肪组织与炎症有关。巨噬细胞可能参与脂肪发育 (21-23)、脂肪储存 (24) 和防止脂肪浪费 (25). 我们在《科学》(Science) 上发表的初步数据 (26) 表明胚胎来源的脂肪组织存在巨噬细胞通过产生 PDGFcc 促进脂肪细胞中的脂质储存，该过程独立于 PDGFcc。骨髓源性巨噬细胞促进炎症和胰岛素抵抗。我们在（目标 1）中的初步数据表明，巨噬细胞是减肥所必需的，因此，在目标 1 中，我将。描绘负责的巨噬细胞谱系 (K99) 并确定巨噬细胞依赖性机制 (R00) 在（目标 2）中，我将确定控制脂质储存的转录基础。我希望通过脂肪组织驻留巨噬细胞使用单核 RNA 测序 (K99) 来推断。控制脂肪储存的细胞电路和下游信号通路的变化。此处确定的分子将在本研究的 R00 阶段使用人类脂肪类器官进行探索，并在在（目标 3）中，我将使用含有人类常驻样巨噬细胞的人类脂肪类器官。为了确认 PDGFcc 在人类脂肪储存中的作用，我发现含有人类脂肪类器官。与无巨噬细胞的脂肪类器官相比，Pdgfc+ 驻留样巨噬细胞会积累更多的脂质。 (R00) 使用这些脂肪类器官来确定巨噬细胞如何影响脂质代谢并确定是否巨噬细胞直接作用于脂肪细胞。此外，人类类器官将用于筛选巨噬细胞。目标 1 和 2 中确定的储能依赖中介。我将继续接受 Frederic 博士的指导盖斯曼（Geissmann），巨噬细胞生物学领域的领军人物。盖斯曼实验室是最早表征我还将受益于我的咨询专业知识。委员会成员包括安东尼·费兰特、克里斯·格拉斯、奥利维尔·克里斯·格拉斯和奥利维尔博士。 Elemento 是备受尊敬的科学家，拥有巨噬细胞和白色脂肪组织分析方面的专业知识通过单细胞方法。我的期望是该提案与我在新陈代谢和脂肪组织功能方面的专业知识相结合。药物开发不仅将提供脂肪组织巨噬细胞的全面功能视图，而且还将提供脂肪组织巨噬细胞的功能。帮助开发可以控制肥胖、脂肪营养不良或恶病质患者肥胖的疗法。