ABSTRACT Liquid biopsy applications are rapidly emerging as a minimally invasive approach to collect system-wide representative analytes for genomic monitoring of physiologic and disease-related changes. Dying cells release fragmented DNA into the circulation, referred to as cell-free DNA (cfDNA). Decoding the cellular origins of cfDNA over time can reveal altered cellular contributions reflective of dynamic changes to tissue damages in longitudinal studies. Here, I will focus on the changes in cellular and tissue homeostasis post liver transplant using molecular analyses of cfDNA. Cell-type specific methylation patterns will be used to trace the cellular origins of cfDNA molecules. In addition, solid organ transplant place a separate DNA set with the donor organ into the body of the host, allowing cfDNA molecules from the allograft to be identified and validated through genotyping using donor-derived SNPs. In this proposal, I aim to track the changing composition of cellular damage post- liver transplant and use this information to improve diagnosis and management of graft dysfunction (Aim 1). During transplant there is simultaneous transfer of tissue-resident immune cells along with the donor organ tissue. I will use immune cell-specific DNA methylation patterns together with the donor SNP analysis to distinguish the host and donor tissue-resident immune cell changes after transplant and during immunosuppressive treatment (Aim 2). The proposed research will evaluate an innovative approach to gain insights into the reaction of host cells, donor organ cells, plus host and donor-immune cells relative to different transplant outcomes. A series of proof- of-principle studies are outlined using liver transplantation as an ideal setup that introduces an organ with a distinct genome at a specific timepoint where there will be induced changes in cell homeostasis to a range of cells in the allografts as well as the host. Beyond the transplant outcome analysis, the cfDNA approach established under this proposal can be expanded to determine the cellular contributions to tissue damages in any setting. Cell type-specific methylation patterns are universal markers that can be used to trace the damaged cell origin of cfDNA irrespective of the cause of damage. Cellular damage in the liver can be due to targeted therapy, chemotherapy, immunosuppression or other interventions, initiation or recurrence of primary liver malignancy, cancer metastatic seeding or organ damage observed during the COVID-19 pandemic. We propose that distinct cellular cfDNA signatures will be observed from different types of injury. Also, there is an unmet need to gain insights into tissue damage during the development of new treatments and understand the cellular basis of adverse events relative to therapeutic efficacy. The global impact of this proposal will be to link cfDNAs in the circulation to their cellular origins and thus reveal drivers of pathophysiology.