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Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis

Award Number: F32AI152348
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis - PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB) and the leading cause of death from a single infectious agent. An estimated 10 million people developed TB disease in 2017, demonstrating an urgent need to new therapeutic approaches, including host-directed therapy (HDT) to halt infection and progression of active TB. Macrophages often serve as the first line of defense against invading pathogens. However, M.tb modulates macrophage cell signaling pathways to induce an environment beneficial to its intracellular survival. The strategies employed by M.tb are an active area of investigation. The overall goal of the laboratory is to identify intracellular master regulators of inflammation and metabolic intermediates that dictate human macrophage responses to M.tb. Previous work in our lab revealed that M.tb interaction with the macrophage mannose receptor (MR) activates peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that dampens the inflammatory response and is associated with increased M.tb growth. The proposed research plan will investigate the hypothesis that MR ligation by M.tb initiates the cAMP signaling pathway leading to PPARγ activation, resulting in enhanced survival of M.tb in macrophages. The Specific Aims are to: 1) Determine the role of phosphodiesterases (PDEs) in regulating PPARγ activity through the cAMP signaling pathway during M.tb infection of hMDMs, 2) Determine the role of Protein Kinase A (PKA) and Exchange Protein Directly Activated by cAMP 1 (Epac1) in regulating PPARγ activity following M.tb-elicited cAMP production in hMDMs, and 3) Determine the effects of MR/cAMP/PKA/Epac1/PPARγ signaling on M.tb pathogenesis. The proposed project will further elucidate the signaling pathway(s) downstream of MR ligation by M.tb, an area only minimally investigated. In addition, this project uses an innovative, newly developed humanized mouse model to study human MR in vivo devoid of the murine MR which is a confounding factor to data analysis. Investigation of the cAMP pathway is expected to identify new, druggable host cell targets for HDT against TB. This research plan affords me the ability to learn new scientific techniques, new models to study infectious diseases, detailed data analysis and the training to shape the direction of this project and my career. The training plan outlines career development activities including opportunities to improve my scientific presentation and communication skills, grantsmanship, mentoring and teaching skills. The research and training will take place at the Texas Biomedical Research Institute with a deep commitment to scientific training, evidenced by numerous journal clubs, seminars and full support of the Texas Biomed Association for Trainees. Texas Biomed has various core facilities, high containment research labs for M.tb work both in vitro and in mice and NHPs, and all resources needed for excellent scientific training. At fellowship completion, I will be prepared to lead a research program in host/pathogen interaction as an independent scientist.


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: 2024 ( Subtotal = $0 )
2024	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	12/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $79,153 )
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	3/21/2022	NON-COMPETING CONTINUATION	$77,793
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	5/23/2022	NON-COMPETING CONTINUATION	$1,360
														Subtotal = $79,153

Issue Date FY: 2021 ( Subtotal = $76,208 )
2021	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	3/10/2021	NON-COMPETING CONTINUATION	$76,208
														Subtotal = $76,208

Issue Date FY: 2020 ( Subtotal = $72,558 )
2020	2020	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	3/10/2020	NEW	$72,558
2020	2020	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	1	3/10/2020	NEW	$0
														Subtotal = $72,558

Grand Total All Awards = $227,919

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Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis

Award Number: F32AI152348

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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