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

总结 2型糖尿病（T2 DM）是一种危及生命的代谢性疾病，可增加结核病的发病率， 在南非和世界范围内的死亡率。葡萄糖稳态失调导致 高血压。在新诊断的T2 DM患者中，高血糖症与TB/T2 DM共 发病率持续性高脂血症导致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， 在肝细胞之后由单核细胞/巨噬细胞产生。我们已经确定了一个转录组签名， 在TB感染中IL-4刺激的巨噬细胞中增加IGF-1。其他研究表明，IGF-1促进 巨噬细胞-IGF-1 R的交替激活和消融阻碍了炎性小体激活， 慢性炎症临床研究表明，高IGF-1水平增加了T2 DM的风险， TB和TB/T2 DM患者血清IGF-1水平。这些研究代表了我们的重大进展， 了解IGF-1并表明宿主免疫的免疫代谢改变会影响结核病的结局， T2 DM和TB/T2 DM。然而，仍有许多工作需要做，如免疫代谢和 IGF-1信号传导中的免疫遗传调节在TB和TB/T2 DM中仍然未知，并且在非洲是一种负担。 更好地进一步了解IGF-1信号介导的免疫代谢失调， 免疫遗传学可以为诊断提供新的生物标志物，并改善患者的治疗选择。 TB、T2DM和TB/T2DM。我假设IGF-1免疫代谢会增加结核病、T2 DM和T2 DM的风险 TB/T2 DM合并症。为了验证这一点，我提出了一个全面的职业发展计划，包括结构化的 活动和指导机会，通过获得高级技能来确定IGF-1的功能（1） 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， 在原代人巨噬细胞中的功能询问;（3）评估IGF-1 R抑制剂作为预防性治疗 在C3 HeB/FeJ小鼠中。 拟议的研究与区域/全球卫生优先事项以及 Pi.该项目的PI，Suraj Parihar博士是南非开普敦大学的免疫学家，他希望 进行研究，以改善在印度长大的患者的生活质量，并亲眼目睹 结核病是一个重大的公共卫生问题。 这个K43奖将使他能够建立一个独立的研究计划，并建立一个独特的科学 巨噬细胞免疫代谢和免疫遗传学的利基，推动创新的诊断和治疗 为发展中国家的患者提供治疗。

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.