Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Each year millions of individuals suffer from heart ailments such as myocardial infarction (MI), myocarditis, cardiomyopathies, etc. that lead to heart failure. Most heart failures are due to the loss of conductivity and contractility secondary to fibrosis that develops as a common response to these cardiac conditions. Early localization of myocardial fibrosis and its resolution is critical to address functional deficit in the failing heart as some types of cardiac fibrosis can be reversed by timely treatment before changes become irreversible. Current diagnostic methods to localize cardiac fibrosis are limited to either myocardial biopsy (invasive, risky, and prone to sampling error) or contrast-magnetic resonance imaging (low sensitivity and only able to detect fibrosis at an advanced and irreversible stage). The objective of this project is to investigate a novel radiotracer 18F-fluoroglucaric acid (18F-FGA) for early detection of cardiac fibrosis by positron emission tomography (PET). PET is a superior imaging technology because of its high resolution, sensitivity, and lack of attenuation. Using molecular techniques, our lab has recently reported that 18F-FGA interacts with an early fibrosis protein called fibronectin. Earlier, we developed a novel rapid technique of synthesizing 18F-FGA from commercially available 18F-fluorodeoxyglucose (18F-FDG), and we reported highly sensitive detection of myocardial infraction and drug-induced cardiomyopathy in preclinical models. The overarching hypothesis of this proposal is that the interaction of 18F-FGA with fibronectin and its distribution in myocardial injury can be exploited to non-invasively detect onset and progress of cardiac fibrosis by PET imaging. We will 1) determine the dynamics of interaction between 18F-FGA and fibronectin (Aim 1); 2) determine time-course of fibronectin accrual in myocardial injury and correlate with 18F-FGA/PET findings (Aim 2), and; 3) assess toxicity and internal dosimetry of 18F-FGA produced by a rapid kit-based method (Aim 3). We will investigate the mechanism of 18F-FGA localization in myocardial injuries, namely MI, drug-induced cardiomyopathy, and myocarditis, by the use of chemical biology approaches and preclinical models. We will also refine the method of 18F-FGA production and quality control to create a kit-based method. We will use the refined kit to determine radiation dosimetry and potential toxicities of FGA for IND-enabling data. Successful implementation of this research will help in clinical translation of 18F-FGA for diagnosis and monitoring of myocardial fibrosis as well as subtle forms of myocardial injury. It will provide cardiologists a window of opportunity to implement treatment and life-style changes to prevent progression to heart failure if cardiac fibrosis is detected early at a reversible stage. In addition, clinical translation of anti-fibrotic agents will be immensely facilitated by the availability of a non-invasive, specific, and sensitive technique to locate and monitor cardiac fibrosis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
