MSTP in PhD Training
Program: Computational and Systems Biology
Current advisor: Kory J. Lavine, MD, PhD
Undergraduate university: California Institute of Technology, 2018
Enrollment year: 2018
Single Cell Multi Omics in Human Coronary Artery Disease and Heart Failure
Cardiovascular disease is the leading cause of death worldwide and is largely driven by atherosclerotic coronary artery disease (CAD) and myocardial infarction (MI) or heart failure (HF). Numerous mechanical and pharmacologic interventions have been developed for the management of CAD and HF, however, the mortality, morbidity, and associated financial healthcare burden stemming from these pathologies remains unacceptably high. Furthermore, genetic variation and ancestral differences strongly associate with cardiovascular disease onset and pathogenesis. One of the challenges to studying CAD and HF is the heterogeneity in disease and imperfect experimental models. The advent of next generation sequencing has afforded us the opportunity to profile healthy and diseased human tissue to uncover pathogenic cell states and molecular pathways driving disease pathogenesis.
Despite tremendous progress in CAD/HF research, we still have an incomplete understanding of the precise cell states, transcriptional programs, and regulatory mechanism driving CAD and HF. I hypothesize that in CAD and HF, infiltrating immune cells enter the coronary artery and myocardium respectively, differentiate into diverse cell states, and interact with and cause resident stromal cells to de-differentiate into reparative and pathogenic cell states. To test this hypothesis, we will employ a reverse translation paradigm: starting with human tissue, we will leverage single cell multiomics to dissect the genomic, transcriptional, and regulatory landscape in CAD and HF to generate experimentally testable hypothesis. Next, we will test a subset of patient derived hypothesis by perturbing the immune-stromal axis in vitro and in vivo to identify potential therapeutic targets.
Bredemeyer AL, Amrute JM, Koenig AL, Idol RA, He L, Luff SA, Dege C, Leid JM, Schilling JD, Hinson JT, Dinauer MC, Sturgeon CM, Lavine KJ. 2022 Derivation of extra-embryonic and intra-embryonic macrophage lineages from human pluripotent stem cells. Development, 149(8):dev200016.
Amrute JM, Perry AM, Anand G, Cruchaga C, Hock KG, Farnsworth CW, Randolph GJ, Lavine KJ, Steed AL. 2022 Cell specific peripheral immune responses predict survival in critical COVID-19 patients. Nat Commun, 13(1):882.
Amrute JM, Zhang D, Padovano WM, Kovács SJ. 2022 E-wave asymmetry elucidates diastolic ventricular stiffness-relaxation coupling: model-based prediction with in vivo validation. Am J Physiol Heart Circ Physiol, 320(1):H181-H189.
Kopecky BJ, Dun H, Amrute JM, Lin CY, Bredemeyer AL, Terada Y, Bayguinov PO, Koenig AL, Frye CC, Fitzpatrick JAJ, Kreisel D, Lavine KJ. 2022 Donor Macrophages Modulate Rejection After Heart Transplantation. Circulation, 146(8):623-638.
Kuppe C, Ramirez Flores RO, Li Z, Hayat S, Levinson RT, Liao X, Hannani MT, Tanevski J, Wünnemann F, Nagai JS, Halder M, Schumacher D, Menzel S, Schäfer G, Hoeft K, Cheng M, Ziegler S, Zhang X, Peisker F, Kaesler N, Saritas T, Xu Y, Kassner A, Gummert J, Morshuis M, Amrute J, Veltrop RJA, Boor P, Klingel K, Van Laake LW, Vink A, Hoogenboezem RM, Bindels EMJ, Schurgers L, Sattler S, Schapiro D, Schneider RK, Lavine K, Milting H, Costa IG, Saez-Rodriguez J, Kramann R. 2022 Spatial multi-omic map of human myocardial infarction. Nature, 608(7924):766-777.
Koenig AL, Shchukina I, Amrute J, Andhey PS, Zaitsev K, Lai L, Bajpai G, Bredemeyer A, Smith G, Jones C, Terrebonne E, Rentschler SL, Artyomov MN, Lavine KJ. 2022 Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat Cardiovasc Res, 1(3):263-280.
Kong W, Biddy BA, Kamimoto K, Amrute JM, Butka EG, Morris SA. 2020 CellTagging: combinatorial indexing to simultaneously map. Nat Protoc, 15(3):750-772.