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

• 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
• 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

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 在美国，每 4 名死亡者中就有 1 人是因消瘦而死亡 (1-3)。尽管数量惊人 死亡人数中，治疗选择仍然有限且不能令人满意。自 20 世纪 90 年代以来的里程碑式研究 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 炎症仍然知之甚少。这一点尤其重要，因为研究表明脂肪组织 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驻留在 巨噬细胞通过产生 PDGFcc 促进脂肪细胞中的脂质储存。这个过程独立于 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) 控制脂肪动员/损失。在（目标 2）中，我将确定控制脂质储存的转录基础 由脂肪组织驻留巨噬细胞使用单核 RNA 测序 (K99) 进行检测。我期望推断出 控制脂肪储存的细胞电路和下游信号通路的变化。候选人 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 体内小鼠模型。在（目标 3）中，我将使用含有人类居民样巨噬细胞的人类脂肪类器官 确认 PDGFcc 在人类脂肪储存中的作用 (K99)。我发现人类脂肪类器官含有 与无巨噬细胞的脂肪类器官相比，Pdgfc+ 驻留样巨噬细胞积累更多的脂质。我会 (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 巨噬细胞的发育谱系和功能。我还将受益于我的顾问的专业知识 委员会成员包括安东尼·费兰特、克里斯·格拉斯和奥利维尔·埃利门托。博士。克里斯·格拉斯和奥利维尔 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。鉴于 Anthony Ferrante 博士是骨髓细胞生物学领域的专家， 新陈代谢和脂肪组织功能。我的期望是，该提案结合我的专业知识 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 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。