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Multiscale modeling of the role of heme during invasive pulmonary aspergillosis

Award Number: R01AI135128
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Multiscale modeling of the role of heme during invasive pulmonary aspergillosis - PROJECT SUMMARY/ABSTRACT Invasive aspergillosis is among the most common fungal infections in immunocompromised hosts and carries a poor outcome. The spores of the causative organism, Aspergillus fumigatus, are ubiquitously distributed in the environment. Healthy hosts clear the inhaled spores without developing disease, but individuals with impaired immunity are susceptible to a life-threatening respiratory infection, during which the fungus invades lung tissues, and can then disseminate to other organs. Aspergillosis is becoming more common and more resistant to antifungal drugs. Current therapeutic approaches have been focused primarily on the pathogen, but a better understanding of the components of host defense in this infection may lead to the development of new treatments against this infection, possibly in combination with antifungal drugs. In the last funding period, we developed a multi–scale computational model of the host response to Aspergillus, and used it as a hypothesis-generating tool to guide experiments to understand mechanisms of iron acquisition during the infection. In the course of these studies, we discovered that the release of extracellular heme as a result of lung hemorrhage during invasive aspergillosis is a key mechanism that promotes fungal growth and virulence. Based on our preliminary data, this renewal application is focused on the inter-connected effects of extracellular heme on both the host and the fungus, and the effect of this on the course of the infection. In Aim 1, we will incorporate the role of heme into our existing multi-scale model of invasive pulmonary aspergillosis, and use the model to mechanistically dissect the contribution of heme to illness progression in the infection, and in Aim 2, we will determine the contribution of extracellular heme release to formation of lung neutrophil extracellular traps and the development of lung injury during invasive aspergillosis. If successful, this project will mechanistically define the central role of extracellular heme in the pathobiology of invasive aspergillosis, and serve as a paradigm for the use of mathematical modeling to integrate complex biological processes and generate rational hypotheses in order to generate new knowledge.


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 = $725,912 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	6	11/19/2024	COMPETING CONTINUATION	$725,912
2025	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	5	2/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $725,912

Issue Date FY: 2022 ( Subtotal = $739,948 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	6/27/2022	NON-COMPETING CONTINUATION	$739,948
														Subtotal = $739,948

Issue Date FY: 2021 ( Subtotal = $748,326 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	4	6/30/2021	NON-COMPETING CONTINUATION	$748,326
2021	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	3	3/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$312,495
2021	2019	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Allergy and Infectious Diseases Research	000	2	3/1/2021	NON-COMPETING CONTINUATION	-$312,495
														Subtotal = $748,326

Issue Date FY: 2020 ( Subtotal = $752,823 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	3	7/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$752,823
2020	2019	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Allergy and Infectious Diseases Research	000	2	7/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $752,823

Issue Date FY: 2019 ( Subtotal = $600,167 )
2019	2019	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Allergy and Infectious Diseases Research	000	2	6/18/2019	NON-COMPETING CONTINUATION	$600,167
														Subtotal = $600,167

Issue Date FY: 2018 ( Subtotal = $619,827 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Allergy and Infectious Diseases Research	000	1	6/27/2018	NEW	$619,827
														Subtotal = $619,827

Grand Total All Awards = $4,187,003

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Multiscale modeling of the role of heme during invasive pulmonary aspergillosis

Award Number: R01AI135128

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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