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The Role of CXCL9 and CXCL10 in Adverse Cardiac Remodeling Following Streptococcus pneumoniae Infection

Award Number: F30HL177982
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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The Role of CXCL9 and CXCL10 in Adverse Cardiac Remodeling Following Streptococcus pneumoniae Infection - PROJECT SUMMARY This NIH F30 application describes a plan for mentored research and career development for the PI, Daniel Minassian. Community-acquired pneumonia (CAP) has increasingly been recognized as a significant risk factor for MACE such as new or worsening heart failure, arrhythmia, and myocardial infarction in hospitalized patients. Streptococcus pneumoniae (Spn) is the leading cause of CAP and models of Spn-induced chronic heart failure have been well-established by the sponsor of this proposal (Dr. Orihuela) in non-human primates and mice. The mechanisms through which Spn infection leads to heart failure are unclear, as it occurs despite appropriate antibiotic therapy, mirroring what is observed clinically; patients who survive treatment for pneumonia are at elevated risk for MACE even 10 years following admission to the hospital. Our preliminary data suggests that post-infection inflammation is causative of cardiac dysfunction as mice treated with a combination of steroids and antibiotics do not suffer reduced ejection fraction, and mice lacking T cells and B cells show a strong trend toward reduced or no chronic cardiac dysfunction following infection. Analysis of RNAseq data obtained from the hearts of mice acutely infected with Spn suggests that the CXCR3 ligands CXCL9 and CXCL10 are particularly upregulated; we have confirmed their production in reporter mice. These chemokines are highly pro-inflammatory and it is the objective of this proposal to determine how CXCL9 and CXCL10 contribute to subsequent heart failure. We hypothesize that CXCL9/10 signaling following pneumonia initiates an inflammatory cascade which leads to chronic inflammation and adverse cardiac remodeling. We will test this hypothesis by examining the impact of Spn infection on CXCL9 and CXCL10 production in the heart (Aim 1) and determining the role of CXCL9/10 signaling in modulating cardiac inflammation and long-term fibrosis (Aim 2). Aim 1 will primarily be accomplished through single nuclear RNA sequencing (snRNAseq) of hearts from infected or antibiotic-treated mice at different times. Aim 2 will be accomplished by blocking CXCL9, CXCL10, and their cognate receptor, CXCR3, through neutralizing antibodies or genetic knockouts and assessing cardiac inflammation through flow cytometry and cardiac damage through echocardiography, histopathology, and relevant biomarkers. All experiments will be performed at the highly funded University of Alabama at Birmingham which is equipped with faculty expertise in Spn and cardioimmunology and all the tools necessary for this proposal. Included in the training plan for the PI are experiences that will support Daniel’s career and professional development, such as 1) rigorous scientific training in the application of advanced flow cytometry, snRNAseq, and next-generation sequencing analysis; 2) presentation of findings at national conferences; 3) continuing clinical education. This proposal drives the development of skills supporting the PI’s future career as a cardiologist-scientist studying how immunological and infectious insults drive the development of heart failure.


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 = $41,233 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	1	8/30/2025	NEW	$0
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	8/30/2025	NEW	$41,233
														Subtotal = $41,233

Grand Total All Awards = $41,233

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The Role of CXCL9 and CXCL10 in Adverse Cardiac Remodeling Following Streptococcus pneumoniae Infection

Award Number: F30HL177982

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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