Molecular Imaging to Guide Repair after Ischemic Damage: Targeting Early Response in the Heart-Brain Axis to Prevent Subsequent Loss of Cardiac and Cognitive Function

• Applicant: Professor James Thackeray, Ph.D.
• Subject Area: Radiology ; Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458617784

The heart and brain form an interdependent symbiotic relationship. Ischemic injury can bear grave consequences for not only the injured organ but also distant reciprocal organs. In patients, incidence of cognitive impairment is elevated after myocardial infarction. Recent evidence indicates that myocardial infarction evokes early cardiac and neuroinflammation, which may contribute to progressive neurodegeneration and cognitive decline. This observation supports a dynamic inflammatory network involving the heart-brain axis, which responds early to ischemic damage and determines long-term functional outcome for both heart and brain. Here, we plan to interrogate this network using serial non-invasive whole-body molecular imaging. This approach will provide not only mechanistic insights into the temporal dynamics of ischemic disease, but also validate image-based guidance of therapeutic targeting and timing. Targeted therapy aims to modify the local tissue environment to support transition from pro-inflammatory to beneficial reparative cell populations or to prevent adverse cell mobilization from hematopoietic reservoirs. Precise timing of therapy enables an appropriate balance between beneficial and harmful inflammation. We hypothesize that temporal information from molecular imaging will guide selective suppression of inflammation at the peak of adverse cell activity following acute ischemic injury, limiting tissue damage in the target and reciprocal organ, and improving long-term cardiac and cognitive outcomes. Our objectives are i) to define the timecourse of cardiac and neuroinflammation after coronary artery ligation in mice and correlate the inflammatory response to later cardiac function and cognitive performance in behavioural testing; ii) to identify the cellular basis of the imaging signal in heart and brain using molecular imaging in conditional knockout animals and cell tracking techniques; iii) to delineate the contribution of specific inflammatory leukocyte subtypes to the local cardiac and reciprocal brain inflammatory response to understand the inter-organ communication; and iv) to utilize the image-based timecourse of adverse inflammation in both organs to guide anti-inflammatory intervention and improve long term outcomes in the heart and brain. This will be tested using a combination of whole body positron emission tomography, molecular biology assays and innovative targeted drugs, with the vision to build a systems biology paradigm for individualized precision reparative therapy.

• DFG Programme: Research Grants