The role of interferon regulatory factors in tanycytes during HFD-induced inflammation, obesity and glucose dysregulation

干扰素调节因子在 HFD 诱导的炎症、肥胖和葡萄糖失调过程中的作用

• 批准号: 10621286
• 负责人: Linus Tzu-Yen Tsai
• 金额: $ 55.1万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621286
• 关键词: ATAC-seq; Address; Adult; Anatomy; Astrocytes; Atlases; Autopsy; Behavior; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; CRISPR/Cas technology; Cell Communication; Cell Line; Cell physiology; Cells; Ceramides; Circulation; Communication; Complex; Continuous Capillary; Cues; Data; Desire for food; Diet; Disparate; Endothelium; Ependymal Cell; Epidemic; Face; Fenestrated Capillary; Fertility; Gene Expression Profiling; Genes; Genetic Models; Genetic study; Glucose; Healthcare Systems; High Fat Diet; Homeostasis; Human; Hypothalamic structure; IRF3 gene; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interferon Activation; Interferons; Lactation; Life; Location; LoxP-flanked allele; MAPK8 gene; Magnetic Resonance Imaging; Mediating; Mediator; Metabolic dysfunction; Methods; Microglia; Modeling; Molecular; Molecular Target; Mus; Neurons; Nutritional; Obesity; Overnutrition; Participant; Pathologic; Pathway Analysis; Pathway interactions; Peripheral; Pharmacological Treatment; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Process; RNA; Regulation; Regulatory Element; Rodent Model; Role; Sentinel; Side; Signal Transduction; Stream; Structure of nucleus infundibularis hypothalami; TLR4 gene; Testing; Therapeutic; Tissues; Transcriptional Activation; Ventricular; Weight Gain; Work; brain parenchyma; cell type; combat; constitutive expression; design; endoplasmic reticulum stress; energy balance; epigenomic profiling; glucose metabolism; improved; insulin sensitivity; knockout gene; median eminence; metabolic phenotype; neurogenesis; obesogenic; passive transport; peripheral blood; progenitor; programs; receptor; response; single cell sequencing; single nucleus RNA-sequencing; single-cell RNA sequencing; transcriptome sequencing

Project Abstract The arcuate nucleus-median eminence complex (Arc-ME) is an evolutionarily conserved region of the hypothalamus that plays important roles in physiology and behavior, including control of appetite, energy balance, insulin sensitivity, fertility and lactation. In rodent models, the initiation of a high fat diet (HFD) rapidly induces inflammation specifically within Arc-ME, well in advance of inflammation observed in peripheral tissues. Genetic studies disrupting this inflammation protect from obesity, suggesting the inflammation is causal, and studies in humans show a correlation between arcuate inflammation and obesity. The arcuate has a unique anatomical relationship with bloodstream, as there is no classic endothelial Blood-Brain-Barrier (BBB) separating it from the median eminence, which is invaginated by fenestrated capillaries that are continuous with the peripheral circulation. Here, tanycytes, specialized ependymal cells found lining the ventricular wall of the basal hypothalamus, extend elaborate processes that separate the Arc and ME, thereby partitioning the ME, CSF, and brain parenchyma into distinct compartments. Studies of hypothalamic inflammation have not previously addressed a role for tanycytes, despite their unique localization. Using single cell RNA-seq, we observe that HFD induces an interferon response pathway specifically in 2 tanycytes, the subpopulation that contacts the peripheral circulation. We hypothesize that 2 tanycytes are sentinel cells that respond to signals associated with HFD by upregulating an inflammatory gene program and initiates hypothalamic inflammation. We propose to test this hypothesis by examining whether genetic models in which the interferon response program is specifically induced or disrupted in tanycytes is sufficient/necessary for induction of hypothalamic inflammation. We further propose to define specific interferon regulatory factor targets by which tanycytes elicit inflammation using a combination of transcriptional and epigenomic profiling within tanycytes and estimation of cell- cell communication from single cell sequencing of our perturbed models. Together, these studies will demonstrate a new role for tanycytes in initiating HFD-induced hypothalamic inflammation and identify specific molecular targets that enable them to do so. As 2 tanycytes are located outside of the BBB, they provide an attractive and specific target cell type modulating energy homeostasis against which to design therapeutics to combat obesity.

项目摘要 弓状核-正中隆起复合体（Arc-ME）是一个进化上保守的区域 在生理和行为中起重要作用的下丘脑，包括控制 食欲、能量平衡、胰岛素敏感性、生育能力和泌乳。在啮齿动物模型中， 高脂饮食（HFD）的快速诱导炎症，特别是在Arc-ME内， 在外周组织中观察到的炎症。遗传学研究破坏这种炎症 防止肥胖，这表明炎症是因果关系，对人类的研究表明， 弓形炎症与肥胖之间的相关性。弓状肌具有独特的解剖学结构 与血流的关系，因为没有经典的内皮血脑屏障（BBB） 将其与正中隆起分开，正中隆起被有孔毛细血管内陷， 与外周循环相连。在这里，我们发现了伸长细胞， 衬在下丘脑基底的心室壁上，延伸出精细的过程， Arc和ME，从而将ME、CSF和脑实质分成不同的区域， 隔间下丘脑炎症的研究以前没有解决的作用， 尽管它们有独特的定位，使用单细胞RNA-seq，我们观察到HFD 特异性地在β 2伸长细胞中诱导干扰素应答途径， 接触外周循环。我们假设，β 2伸长细胞是哨兵细胞， 通过上调炎症基因程序对HFD相关信号作出反应， 引发下丘脑炎症我们建议通过检查是否 干扰素应答程序被特异性诱导或破坏的遗传模型， 伸长细胞对于诱导下丘脑炎症是足够的/必需的。我们进一步建议 使用本发明的方法来确定伸长细胞引起炎症的特异性干扰素调节因子靶点， 在伸长细胞内的转录和表观基因组谱分析的组合和细胞- 从我们的扰动模型的单细胞测序的细胞通信。这些研究一起 将证明伸长细胞在引发HFD诱导的下丘脑炎症中的新作用 并确定特定的分子目标，使他们能够这样做。由于102个伸长细胞位于 在BBB外，它们提供有吸引力的和特异性的靶细胞类型调节能量 体内平衡来设计治疗肥胖的方法。