Myeloid lineage activation and reprogramming in metabolic dysfunction

代谢功能障碍中的骨髓谱系激活和重编程

• 批准号: 10242720
• 负责人: Lindsey Allison Muir
• 金额: $ 9.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242720
• 关键词: Adipose tissue; Affect; Architecture; Area; Artificial nanoparticles; Attenuated; Bioinformatics; Biological Assay; Blood; Blood Circulation; Cardiovascular Diseases; Cells; Cellular Assay; Chromosomes; Clinical; Clinical Research; Collaborations; Data; Development; Diabetes Mellitus; Disease; Drug Delivery Systems; Endocytosis; Flow Cytometry; Functional disorder; Gene Delivery; Genes; Genetic Transcription; Genomics; Goals; Health; Hi-C; High Prevalence; Human; Immune; Immune Tolerance; Immunology; Inflammation; Inflammation Mediators; Inflammatory; Insulin Resistance; International; Investigation; Knowledge; Link; Macrophage Activation; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic Diseases; Metabolic dysfunction; Methods; Molecular; Mus; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Nanotechnology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Pathway interactions; Phenotype; Polymers; Population; Production; Regenerative Medicine; Research; Research Personnel; Research Training; Risk; Specificity; Technology; Testing; Training; Translations; bariatric surgery; base; bioinformatics tool; cell type; cohort; cost; cost effective; cytokine; diabetic; diabetic patient; disorder risk; experience; genomic platform; large datasets; macrophage; monocyte; nanomaterials; nanoparticle; new therapeutic target; non-diabetic; novel; particle; peripheral blood; programs; scavenger receptor; skills; therapeutic nanoparticles; therapeutic target; transcriptome sequencing

PROJECT SUMMARY The high prevalence and health impact of obesity drives a critical need to understand the link between obesity and disease. Monocyte and macrophage activation that contributes to low grade inflammation is one such link. These myeloid cells contribute to inflammation by producing proinflammatory cytokines, activating other immune cells, and monocytes can also differentiate into proinflammatory macrophages, all of which are associated with insulin resistance. However, the mechanisms underlying myeloid cell proinflammatory activation in human obesity and diabetes are not resolved. My preliminary data identify lysosomal dysfunction in SRhi myeloid cells as high priority targets for investigation in diabetes. Furthermore, strategies to alleviate inflammation in metabolic disease have been ineffective, partly due to low cellular specificity. We identify polymer nanoparticles (NPs) as excellent candidates for a more specific approach. My preliminary data show increased NP-monocyte interactions in obese diabetic patients vs. non-diabetic, making NPs a promising approach for targeting myeloid cells in diabetes. My central hypothesis is that obesity disrupts SRhi myeloid cell lysosomal processing, increasing production of inflammatory mediators, and that NPs can modulate SRhi myeloid cell inflammatory activation. To examine this hypothesis, I will use monocytes and ATMs from a valuable obese bariatric surgery cohort, focusing on diabetic vs. non-diabetic comparisons in two research aims: (1) Identify the genes and pathways by which myeloid cells are dysregulated in human obesity. I will use a combination of powerful, unbiased high-throughput genomics platforms with novel bioinformatics tools to identify specific pathways and regulators in SRhi myeloid cells from diabetic patients. I will use assays of endocytosis and lysosomal function, proinflammatory cytokines, and flow cytometry to determine functional changes in SRhi myeloid cell subtypes in diabetes. (2) Determine the specificity and efficacy of NPs for myeloid cell modulation in human obesity. I will test internalization and impact of NPs on human SRhi myeloid cell subtypes, determining whether they can attenuate proinflammatory signatures through cytokine assays and RNA-seq. By completing these aims I will identify the molecular and cellular signatures mediating activation of SRhi myeloid cells and determine efficacy of novel NP-therapeutics to modulate SRhi myeloid cells in human metabolic disease. I will gain expertise in nanotechnology and high-throughput genomics platforms. The mentorship team will be led by co-primary mentors Dr. Robert O'Rourke and Dr. Lonnie Shea. Dr. O'Rourke is an expert in human obesity and clinical biosamples. Dr. Shea is an internationally recognized researcher at the interface of regenerative medicine, drug and gene delivery, and immune tolerance. Co-primary mentors and experts in immunometabolism, diabetes, obesity, and genomics and bioinformatics will guide me in completing the research and training proposed. Completing these goals will be a critical step toward independent research in translational immunology and immunometabolism.

项目摘要 肥胖的高流行和健康影响驱动了了解肥胖之间联系的迫切需求 和疾病。导致低年级炎症的单核细胞和巨噬细胞激活就是这样的联系。 这些髓样细胞通过产生促炎细胞因子，激活其他细胞来导致炎症 免疫细胞和单核细胞也可以分化为促炎性巨噬细胞，所有这些都是 与胰岛素抵抗有关。但是，髓样细胞促炎的基础机制 人类肥胖症和糖尿病的激活无法解决。我的初步数据识别溶酶体功能障碍 在SRHI髓样细胞中，作为糖尿病研究的高优先级靶标。此外，减轻策略 代谢疾病的炎症无效，部分是由于细胞特异性低。我们确定 聚合物纳米颗粒（NP）作为更具体方法的优秀候选物。我的初步数据显示 肥胖糖尿病患者与非糖尿病的NP单细胞相互作用增加了，使NP成为有前途的 靶向糖尿病中髓样细胞的方法。我的中心假设是肥胖会破坏SRHI髓样细胞 溶酶体加工，炎症介质的产生增加，NP可以调节SRHI 髓样细胞炎症激活。为了审查这一假设，我将使用来自 有价值的肥胖减肥手术队列，重点介绍两项研究的糖尿病与非糖尿病比较 目的：（1）确定人肥胖症中髓样细胞失调的基因和途径。我会用 强大的，公正的高通量基因组学平台与新型生物信息学工具的结合 确定来自糖尿病患者的SRHI髓样细胞中的特定途径和调节剂。我将使用测定 内吞作用和溶酶体功能，促炎细胞因子和流式细胞仪，以确定功能 糖尿病中SRHI髓样细胞亚型的变化。 （2）确定NP对髓样的特异性和功效 人肥胖中的细胞调节。我将测试NP对人SRHI髓样细胞的内在化和影响 亚型，确定它们是否可以通过细胞因子测定和 RNA-seq。通过完成这些目标，我将确定介导的激活的分子和细胞特征 SRHI髓样细胞并确定新型NP-治疗药在人类中调节SRHI髓样细胞的功效 代谢疾病。我将获得纳米技术和高通量基因组学平台方面的专业知识。这 导师团队将由联合主导的罗伯特·奥罗克（Robert O'Rourke）博士和朗尼·谢伊（Lonnie Shea）博士领导。 O'Rourke博士是 人类肥胖和临床生物样本的专家。 Shea博士是国际认可的研究人员 再生医学，药物和基因递送以及免疫耐受性的界面。联合促进导师和 免疫代谢，糖尿病，肥胖和基因组学和生物信息学专家将指导我完成 提出的研究和培训。完成这些目标将是迈向独立研究的关键一步 在转化免疫学和免疫代谢中。