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.

项目概要 肥胖的高患病率和对健康的影响迫切需要了解肥胖之间的联系 和疾病。导致低度炎症的单核细胞和巨噬细胞激活就是其中之一。 这些骨髓细胞通过产生促炎细胞因子、激活其他细胞因子而导致炎症。 免疫细胞和单核细胞也可以分化为促炎巨噬细胞，所有这些都是 与胰岛素抵抗有关。然而，骨髓细胞促炎症的机制 人类肥胖和糖尿病中的激活尚未得到解决。我的初步数据表明溶酶体功能障碍 SRhi 骨髓细胞作为糖尿病研究的高度优先目标。此外，缓解策略 炎症在代谢疾病中一直无效，部分原因是细胞特异性低。我们确定 聚合物纳米颗粒（NP）是更具体方法的优秀候选者。我的初步数据显示 与非糖尿病患者相比，肥胖糖尿病患者的 NP-单核细胞相互作用增加，这使得 NP 成为一种有前途的药物 糖尿病靶向骨髓细胞的方法。我的中心假设是肥胖会破坏 SRhi 骨髓细胞 溶酶体加工、增加炎症介质的产生以及 NP 可以调节 SRhi 骨髓细胞炎症激活。为了检验这个假设，我将使用来自 有价值的肥胖减肥手术队列，重点关注两项研究中糖尿病与非糖尿病的比较 目标：（1）确定骨髓细胞在人类肥胖中失调的基因和途径。我会用 强大、公正的高通量基因组学平台与新颖的生物信息学工具的结合 鉴定糖尿病患者 SRhi 骨髓细胞的特定通路和调节因子。我将使用以下分析 内吞作用和溶酶体功能、促炎细胞因子和流式细胞术以确定功能 糖尿病中 SRhi 骨髓细胞亚型的变化。 (2) 确定NPs对骨髓的特异性和有效性 人类肥胖中的细胞调节。我将测试 NP 对人类 SRhi 骨髓细胞的内化和影响 亚型，通过细胞因子测定确定它们是否可以减弱促炎特征 RNA测序。通过完成这些目标，我将识别介导激活的分子和细胞特征 SRhi 骨髓细胞并确定新型 NP 疗法调节人类 SRhi 骨髓细胞的功效 代谢性疾病。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 导师团队将由联合首席导师 Robert O'Rourke 博士和 Lonnie Shea 博士领导。奥罗克博士是 人类肥胖和临床生物样本方面的专家。 Shea 博士是国际公认的研究员 再生医学、药物和基因传递以及免疫耐受的界面。共同主要导师和 免疫代谢、糖尿病、肥胖、基因组学和生物信息学专家将指导我完成 拟议的研究和培训。完成这些目标将是迈向独立研究的关键一步 翻译免疫学和免疫代谢。