This research program aims to bridge the gap between genomics data generation from clinical samples and our ability to infer and interpret intricate regulatory programs that underpin cell function and dysfunction in human cells. The Ucar laboratory develops and applies computational solutions to uncover complex regulatory programs in human cells and address previously inaccessible questions related to how disruptions in these programs affect human health and disease. The goal is to create computational tools that are versatile, easy to use and in keeping with the ever-increasing sophistication and complexity of NGS data. The current focus on the immunobiology of aging leverages the Principal Investigator's extensive training in computer science, epigenomics, and aging biology. Ongoing work with collaborators at The Jackson Laboratory and The University of Connecticut Health Center has led to multiple discoveries related to the genomic signatures of human immune aging, and has yielded numerous questions that form the basis for the proposed research program, including: 1) Which regulatory programs and regulatory interactions are disrupted with aging in which immune cells? 2) How do men and women age differently? 3) What are the putative genomic/clinical/immunological markers of healthy aging? To address these questions, this research program will focus on developing machine learning and network mining algorithms that enable integration of data from diverse sources, since complex regulatory interactions and diverse regulatory elements cannot be inferred from a single data type. Fueled by these tools, it will investigate the dynamics of regulatory programs in blood- derived human immune cells associated with aging through collaborations with clinicians, immunologists, and chromatin scientists. This research will advance our understanding of how immune responses are transcriptionally regulated, will facilitate the design of interventions to boost immune health in elderly and diseased individuals, and will yield computational resources useful to diverse areas of genomic medicine.

Public Health Relevance

The declining responsiveness of the aging immune system to combat infection is a major threat to the health, independence and survival of older adults. Here we propose to develop novel informatics tools and generate novel epigenomic data to investigate the regulatory mechanisms of the human immune system associated with aging. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM124922-01
Application #
9382313
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ravichandran, Veerasamy
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Justice, Jamie N; Ferrucci, Luigi; Newman, Anne B et al. (2018) A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. Geroscience 40:419-436
Thibodeau, Asa; Uyar, Asli; Khetan, Shubham et al. (2018) A neural network based model effectively predicts enhancers from clinical ATAC-seq samples. Sci Rep 8:16048
Youn, Ahrim; Marquez, Eladio J; Lawlor, Nathan et al. (2018) BiFET: sequencing Bias-free transcription factor Footprint Enrichment Test. Nucleic Acids Res :
Lee, Donghyung; Cheng, Anthony; Lawlor, Nathan et al. (2018) Detection of correlated hidden factors from single cell transcriptomes using Iteratively Adjusted-SVA (IA-SVA). Sci Rep 8:17040
Ahmed, Zeeshan; Ucar, Duygu (2017) I-ATAC: interactive pipeline for the management and pre-processing of ATAC-seq samples. PeerJ 5:e4040
Thibodeau, Asa; Márquez, Eladio J; Shin, Dong-Guk et al. (2017) Chromatin interaction networks revealed unique connectivity patterns of broad H3K4me3 domains and super enhancers in 3D chromatin. Sci Rep 7:14466