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.

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