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

Award Number: K43TW012587
ORGANIZATION: FOGARTY INTERNATIONAL CENTER
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $112,467 )
2025	2025	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	International Research and Research Training	000	3	7/24/2025	NON-COMPETING CONTINUATION	$112,467
														Subtotal = $112,467

Issue Date FY: 2024 ( Subtotal = $112,504 )
2024	2024	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	International Research and Research Training	000	2	4/4/2024	NON-COMPETING CONTINUATION	$112,504
														Subtotal = $112,504

Issue Date FY: 2023 ( Subtotal = $112,586 )
2023	2023	REDACTED DUE TO PII		CAPE TOWN				ZAF	International Research and Research Training	000	1	7/17/2023	NEW	$112,586
														Subtotal = $112,586

Grand Total All Awards = $337,557

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

Award Number: K43TW012587

ORGANIZATION: FOGARTY INTERNATIONAL CENTER

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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