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) 是一种危及生命的代谢性疾病，会增加结核病的发病率和 南非和全世界的死亡率。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 共存相关 发病率。持续高血糖会导致患者对胰岛素样生长因子-1 (IGF-1) 的敏感性增强 血管内皮细胞和平滑肌细胞。 IGF-1 影响先天免疫系统，并且主要影响 由肝细胞之后的单核细胞/巨噬细胞产生。我们已经确定了转录组签名 TB 感染中 IL-4 刺激的巨噬细胞中 IGF-1 增加。其他研究表明 IGF-1 可以促进 巨噬细胞-IGF-1R的替代激活和消融阻碍炎性体激活以减少 慢性炎症。临床研究表明，高 IGF-1 水平会增加患 T2DM 的风险，并增加 TB 和 TB/T2DM 患者的血清 IGF-1 水平。这些研究代表了我们在 了解 IGF-1 并表明宿主免疫中的免疫代谢改变会影响结核病的结果， T2DM 和 TB/T2DM。然而，在免疫代谢和免疫代谢方面仍有许多工作需要完成。 IGF-1 信号传导中的免疫遗传学调控在结核病和结核病/T2DM 中仍然未知，并且是非洲的负担。 更好地进一步了解 IGF-1 信号传导介导的免疫代谢失调和 免疫遗传学可以为诊断提供新的生物标志物，并改善患有以下疾病的患者的治疗选择 结核病、T2DM 和 TB/T2DM。我假设 IGF-1 免疫代谢会增加患 TB、T2DM 和 TB/T2DM 共病。为了测试这一点，我提出了一个全面的职业发展计划，其中包括结构化的 通过获得 (1) 方面的高级技能来确定 IGF-1 功能的活动和指导机会 患者样本的代谢研究； (2) 生物信息学，用于识别临床数据集中的遗传变异； 原代人类巨噬细胞的功能研究； (3) 评估 IGF-1R 抑制剂作为辅助治疗的作用 在 C3HeB/FeJ 小鼠中。 拟议的研究与区域/全球卫生优先事项以及职业发展高度相关 PI。项目负责人 Suraj Parihar 博士是南非开普敦大学的免疫学家，他希望 进行研究，以改善在印度长大并亲眼目睹了印度疾病的患者的生活质量 结核病作为一个重大公共卫生问题的影响。 该 K43 奖项将使他能够建立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领域的利基推动创新诊断和治疗 针对发展中国家患者的治疗方法。