PROJECT SUMMARY We propose to strengthen and extend the research capacity of the COBRE Center for the Computational Biology of Human Disease (CBHD) at Brown University and affiliated hospitals. High throughput data from multiple ‘omics-level’ technologies are fundamental factors in the identification and treatment of human disease. The acquisition of these data is now straightforward, but the efficient and creative interpretation of these data remain a serious impediment to progress for junior faculty in both the basic and translational aspects of biomedical science. The underlying principle of this Center is that close collaboration between laboratory scientists working with model systems and data scientists working with computational and bioinformatics tools can accelerate the implementation of human disease research. In Phase 1, we established the CBHD COBRE around a Computational Biology Core (CBC) and support for junior faculty Project Leaders (9) and Pilots Project leaders (8). These Project Leaders have been awarded six NIH R01s, an R35 MIRA, an NIH T32 Training Grant, an NIH R21, a USDA grant, a Sloan Award, and a Searle Award, totaling ~$17.9M. In Phase 2 we will strengthen this research environment with support for four new Project Leaders and a plan for growth and sustainability of the CBC that serves as the analysis and training hub of this COBRE. Our innovative joint mentoring strategy where each Project Leader is advised by both computational and biological or clinical senior faculty members has proven successful, and this will be extended. Moreover, we will build sustainable support for the CBC through expanded collaboration with COBRE graduates and other faculty on external grant support plus internally funded staff data scientists. The long-term goal of the Center is to grow a nexus of computational biology infrastructure for the greater Brown and hospital environments that will benefit all of Rhode Island. The objective of this proposal is to strengthen the infrastructure of the CBHD COBRE to ensure the transition of junior faculty Project Leaders to R01-funded scientists, and raise the computational proficiency and diversity of the broader biomedical research community. The three Aims are: Aim 1. Support the research of junior faculty Project Leaders pursuing biological and computational approaches to human disease. Aim 2. Broaden the CBHD research environment through enhanced Pilot and Mentoring programs that increase faculty recruitment and promote funding independence for Project Leaders. Aim 3. Strengthen the Computational Biology Core through enhanced staffing and broader access across the Brown biomedical community to build sustainability. The four new Research Projects are: 1. Local Regulation of T-cell Differentiation and Function in the Reproductive Mucosa; 2: Profiling Gene Expression and Mechanophenotype in Circulating Tumor Cells Ex Vivo; 3: Mapping Long-range Allosteric Pathways in CRISPR-Cas9; 4: Modeling Long-ran...