Insulin-like Growth Factor-1 (IGF-1) signalling in immunometabolism of TB and TB-Diabetes comorbidity

胰岛素样生长因子-1 (IGF-1) 信号在结核病和结核病-糖尿病合并症免疫代谢中的作用

• 批准号: 10734113
• 负责人: Suraj P. Parihar
• 金额: $ 11.26万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734113
• 关键词: Ablation; Address; Africa; Alternative Therapies; Automobile Driving; Award; Bioinformatics; Biological Markers; C3HeB/FeJ Mouse; Cause of Death; Cells; Chronic; Clinical; Clinical Data; Clinical Research; Collaborations; Communities; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Diagnostic; Disease; Exhibits; Flow Cytometry; Functional disorder; Genes; Genetic; Genetic Polymorphism; Growth; HIV; Health Priorities; Hepatocyte; Human; Human Genetics; IGF1R gene; Immune; Immune Sera; Immune Targeting; Immune response; Immunity; Immunogenetics; Immunologist; Incidence; India; Individual; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Innovative Therapy; Insulin-Like Growth Factor I; Interleukin-4; Life; Link; Macrophage; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mycobacterium tuberculosis; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Positioning Attribute; Predisposition; Public Health; Published Database; Publishing; Pulmonary Tuberculosis; Quality of life; Quantitative Trait Loci; Regulation; Research; Research Support; Resistance; Resources; Risk; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; South Africa; Structure; Testing; Therapeutic; Time; Training; Tuberculosis; Universities; Vascular Endothelium; Work; biobank; blood glucose regulation; career development; cohort; comorbidity; cytokine; diet-induced obesity; disorder risk; genetic variant; genomic locus; global health; improved; in vivo; inhibitor; innovation; insight; insulin regulation; low and middle-income countries; lung lesion; metabolic abnormality assessment; metabolic profile; monocyte; mortality; mouse model; novel; programs; repository; response; skills; targeted treatment; transcriptomics

Summary Type 2 diabetes mellitus (T2DM), is a life-threatening metabolic disease that increases TB incidence and mortality in South Africa and Worldwide. Dysregulation of glucose homeostasis leads to the development of hyperglycaemia. Amongst newly diagnosed T2DM patients, hyperglycaemia is associated with TB/T2DM co- morbidity. Sustained hyperglycaemia results in enhanced sensitivity to Insulin-like Growth Factor-1 (IGF-1) in vascular endothelial and smooth muscle cells. IGF-1 influence the innate immune system and predominantly produced by monocytes/macrophages after hepatocytes. We have identified a transcriptomic signature of increased IGF-1 in IL-4-stimulated macrophages in TB infection. Others have shown that IGF-1 facilitates alternative activation and ablation of macrophage-IGF-1R hampers the inflammasome activation to reduce chronic inflammation. Clinical studies revealed that high IGF-1 levels increased the risk of T2DM and increased serum IGF-1 levels in patients with TB and TB/T2DM. These studies represent significant advances in our understanding of IGF-1 and suggest altered immunometabolism in host immunity influencing the outcome of TB, T2DM and TB/T2DM. However, there is still much work that needs to be done as immunometabolic and immunogenetic regulations in IGF-1 signalling remain unknown in TB and TB/T2DM and a burden in Africa. A better further understanding of the IGF-1 signalling-mediated dysregulation of immunometabolism and immunogenetics could inform new biomarkers for diagnostics and improve treatment options for patients with TB, T2DM and TB/T2DM. I hypothesize that IGF-1 immunometabolism increases the risk of TB, T2DM and TB/T2DM co-morbidity. To test this, I propose a comprehensive career development plan comprising structured activities and mentorship opportunities to determine the function of IGF-1 by acquiring advanced skills in (1) metabolic studies in patient samples; (2) bioinformatics to identify genetic variants in clinical datasets and functional interrogations in primary human macrophages; (3) assess an IGF-1R inhibitor as adjunctive therapy in the C3HeB/FeJ mice. The research proposed is highly relevant to regional/global health priorities, and the career development of the PI. The project PI, Dr Suraj Parihar, is an immunologist at the University of Cape Town, South Africa, that wants to conduct research that will improve life quality of patients having grown up in India and seen first-hand the impact of TB as a significant public health problem. This K43 award will position him to build an independent program of research and establish a unique scientific niche in macrophage immunometabolism and immunogenetics that drives innovative diagnostic and therapeutic approaches for patients in developing world.

概括 2型糖尿病（T2DM）是一种威胁生命的代谢疾病，可增加结核病的发生率和 南非和全球的死亡率。葡萄糖稳态失调导致 高血糖。在新诊断的T2DM患者中，高血糖与TB/T2DM共同 发病率。持续的高血糖导致对胰岛素样生长因子1（IGF-1）的敏感性增强 血管内皮和平滑肌细胞。 IGF-1主要影响先天免疫系统，主要影响 肝细胞后由单核细胞/巨噬细胞产生。我们已经确定了一个转录组签名 在结核病感染中，IL-4刺激的巨噬细胞中的IGF-1增加。其他人表明IGF-1有助于 巨噬细胞-IGF-1R的替代激活和消融会阻碍炎症体激活以减少 慢性炎症。临床研究表明，高IGF-1水平增加了T2DM的风险并增加了 TB和TB/T2DM患者的血清IGF-1水平。这些研究代表了我们的重大进步 了解IGF-1，并建议改变宿主免疫的免疫代谢，从而影响结核病结果的宿主免疫。 T2DM和TB/T2DM。但是，仍然需要做很多工作，以作为免疫代谢和 IGF-1信号传导中的免疫遗传法规在TB和TB/T2DM中尚不清楚，非洲的负担。 更好地了解IGF-1信号介导的免疫代谢的失调和 免疫遗传学可以为新的生物标志物提供诊断的新生物标志物，并改善 TB，T2DM和TB/T2DM。我假设IGF-1免疫代谢增加了TB，T2DM和 TB/T2DM合并症。为了测试这一点，我提出了一个全面的职业发展计划，包括结构化 通过（1）中获得高级技能来确定IGF-1功能的活动和指导机会 患者样本中的代谢研究； （2）生物信息学以识别临床数据集中的遗传变异 原代人巨噬细胞的功能审查； （3）评估IGF-1R抑制剂作为辅助治疗 在C3HEB/FEJ小鼠中。 提出的研究与区域/全球健康的重点高度相关，以及 pi。 PI Project Pi Suraj Parihar博士是南非开普敦大学的免疫学家 进行研究，以改善印度成长的患者的生活质量，并亲眼目睹 结核病作为重大公共卫生问题的影响。 这个K43奖将使他构建一个独立的研究计划，并建立独特的科学 巨噬细胞免疫代谢和免疫遗传学中的利基市场，这些动力驱动创新的诊断和治疗性 发展中国家患者的方法。