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Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB)

Award Number: R01AI173946
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB) - PROJECT SUMMARY Tuberculosis (TB) is the 2nd leading cause of infectious disease mortality worldwide with ~1.5 million deaths in 2020. A hallmark of pulmonary TB is the propensity to form cavitary lesions in ~30-85% of patients. Cavities provide an ideal environment for Mycobacterium tuberculosis (Mtb) replication, are associated with decreased penetration of antibiotics, and can lead to irreversible lung damage. Importantly, they are associated with poor clinical outcomes including acquired drug resistance and treatment failure. Cavities develop from progression of necrotic lung granulomas; however, mechanisms underlying their formation are not clear. Improved understanding of the inflammatory responses that drive tissue necrosis and the ability of antibiotics to achieve therapeutic concentrations within necrotic granulomas are needed to 1) identify targets for host directed therapies (HDT) that can limit tissue damage and 2) to optimize antibiotic regimens. Utilizing innovative methods in imaging and spatial multiomics, we will map the distribution of transcriptional pathways and biomediators associated with human necrotic granulomas and cavities and of newly implemented anti-TB drugs in such lesions with an overall goal of providing critical new data to improve TB treatment The long term objective of this research is to provide data to guide development of a tandem therapeutic approach of optimizing anti-TB drug regimens based on their ability to reach bactericidal concentrations in all lesion areas combined with host-targeted therapies to limit pathologic inflammation. The specific aims of this proposal are to (1) identify the host metabolic and lipid phenotypes associated with each tissue region of human necrotic lung granulomas; (2) utilize spatial transcriptomics and targeted imaging to identify pathological programs associated with tissue necrosis in necrotic granulomas; and (3) utilize target site pharmacokinetics (PK) and PK modeling to enhance understanding of newly implemented anti-TB drugs. The aims of this project will be achieved by enrolling a unique cohort of patients with pulmonary TB undergoing adjunctive surgery and subsequent study of their resected lung lesions. Scientific methods employed to carry out our aims include the use of enhanced MALDI-2 mass spectrometry imaging (MSI), laser capture microdissection (LCM) to isolate targeted granulomas regions for high-resolution metabolomics, lipidomics and drug concentration assays, and novel spatial transcriptomics and advanced data analytic methods to integrate spatially resolved multi-omics data sets and model target site PK data. This proposal will directly address key priories in the TB research agenda including attaining a better understanding of the determinants of M. tuberculosis control in granulomas and how anti-TB drugs localize and penetrate into granulomas and cavities. Specific goals of the proposed work are to identify host inflammatory pathways that can be exploited for host-directed therapy and to define tissue penetrating properties of key drugs used for drug-resistant TB to optimize drug regimen design for clinical trial testing and treatment.


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 = $762,816 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	3	2/13/2025	NON-COMPETING CONTINUATION	$762,816
														Subtotal = $762,816

Issue Date FY: 2024 ( Subtotal = $762,667 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$76,267
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	1/24/2024	NON-COMPETING CONTINUATION	$686,400
														Subtotal = $762,667

Issue Date FY: 2023 ( Subtotal = $813,868 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	1	6/28/2023	NEW	$11,880
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	2/9/2023	NEW	$801,988
														Subtotal = $813,868

Grand Total All Awards = $2,339,351

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Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB)

Award Number: R01AI173946

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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