Project Summary/Abstract Dr Sharmila Dorbala is an Associate Professor of Radiology at Harvard Medical School and a physician/scientist at Brigham and Women's Hospital (BWH). She has devoted her career to patient-oriented research focusing on cardiac amyloidosis. She contributed independently to the field of cardiac amyloidosis through a succession of substantive studies utilizing molecular imaging to phenotype cardiac amyloidosis in order to diagnose and manage this condition. Her research program is impactful, both directly and through effective mentoring of the next generation of amyloidosis investigators. Dr. Dorbala has successfully mentored 26 pre- and post-doctoral trainees in patient- oriented research projects. She is currently PI of two active NIH R01 grants and also has funding from AHA and foundation/industrial sources. Her program provides a unique opportunity for POR due to the intersection of resources from programs in clinical investigation at the Harvard School of Public Health and the BWH cardiovascular imaging T32 program. Her mentees have presented their work nationally and internationally, published papers, and won research awards and pilot grants. The new research aims proposed in this award lay the foundation for adjunct interventions to enhance transthyretin cardiac amyloidosis (ATTR-CA) therapies and novel image-based personalized strategies to predict treatment failure. She will assess (1) sonoporation, a therapeutic ultrasound technique to increase myocardial perfusion and, consequently, improve delivery of antifibril drugs; (2) shotgun metagenomic sequencing of the gut microbiome to inform development of nutrition-based adjunct therapies; (3) radiomics of 99mTc- pyrophosphate SPECT/CT to assess treatment response, and (4) machine learning based CT-derived sarcopenia metric to predict survival. This research has important clinical implications. Currently approved TTR stabilizing/silencing drugs, though lifesaving for most, are not effective in about 30% of patients. Moreover, while these therapies improve clinical outcomes, they do not treat amyloid fibril. Fibril-targeted therapies have been unsuccessful to date, probably because of poor interstitial drug delivery due to the presence of fibril. The results of the proposed mentoring and research activities of this K24 project are likely to not only substantially improve outcomes and alleviate HF symptoms in these gravely ill patients, but also transform her patient- oriented research program into a formal individualized program of mentoring with a focus on preventing heart failure from amyloidosis.