Decoding the Tissue of Origin of Cellular Damage from Cell-free DNA in Liquid Biopsies

从液体活检中的游离 DNA 解码细胞损伤的组织起源

• 批准号: 10441196
• 负责人: Megan Evelyn Barefoot
• 金额: $ 3.41万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441196
• 关键词: Acute; Adverse event; Allografting; Apoptosis; Area; Biliary; Biological; Biopsy; Blood Circulation; Blood Vessels; Blood specimen; COVID-19 pandemic; Cell Death; Cells; Cessation of life; Characteristics; Chimerism; Clinical; DNA; DNA Methylation; Data; Death Rate; Decision Making; Detection; Development; Diagnosis; Diagnostic; Disease; Disseminated Malignant Neoplasm; Endothelium; Engraftment; Enzymes; Exhibits; Frequencies; Functional disorder; Genetic; Genome; Genomics; Genotype; Goals; Hepatic; Hepatocyte; Heterogeneity; Homeostasis; Human; Human body; Immune; Immunosuppression; Immunosuppressive Agents; Infection; Injury; Intervention; Link; Liver; Liver Circulation; Liver Function Tests; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Medicine; Methylation; Molecular; Molecular Analysis; Monitor; Morphology; Necrosis; Organ; Organ Donor; Organ Transplantation; Outcome; Pathologic; Physiologic Monitoring; Physiological; Population; Process; Proteins; Reaction; Recurrence; Reperfusion Injury; Research; Resources; Role; Sampling; Series; Serum; Solid; Surgical complication; System; Therapeutic; Therapeutic Intervention; Time; Tissue Donors; Tissues; Transplant Recipients; Transplantation; Treatment Efficacy; base; cell free DNA; cell injury; cell type; chemotherapy; cholangiocyte; clinical decision-making; clinically significant; genome sequencing; graft dysfunction; improved; innovation; insight; liquid biopsy; liver biopsy; liver injury; liver transplantation; longitudinal analysis; methylation biomarker; methylation pattern; methylome; minimally invasive; novel; prenatal testing; residence; targeted treatment; tool; transcriptome sequencing; whole genome

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.

摘要

项目成果

Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma.

• DOI: 10.3389/fgene.2021.708326
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Varghese RS;Barefoot ME;Jain S;Chen Y;Zhang Y;Alley A;Kroemer AH;Tadesse MG;Kumar D;Sherif ZA;Ressom HW
• 通讯作者: Ressom HW

Detection of Cell Types Contributing to Cancer From Circulating, Cell-Free Methylated DNA.

• DOI: 10.3389/fgene.2021.671057
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Barefoot ME;Loyfer N;Kiliti AJ;McDeed AP 4th;Kaplan T;Wellstein A
• 通讯作者: Wellstein A