PROJECT SUMMARY Nicole Prince, PhD is a biochemist with expertise in applying molecular epidemiology analytic approaches to understand complex diseases. Her overarching career goal is to become an independent researcher with a skill set across multiple ‘omics to improve understanding of the biological determinants underlying respiratory infection risk, one of the leading causes of mortality in children <5 years (YR) of age. The proposed research plan leverages her background in biochemistry and analytical chemistry with new training in immunology, respiratory medicine, and multi-omic methods, to enhance her ability to study the complex, heterogeneous environment that underlies infection susceptibility during the first few years of life. Evidence suggests there are genetic and epidemiological drivers of susceptibility across different subsets of children, but these cannot fully explain the observed inter-individual variability in respiratory infection risk; and, the hypothesis of this proposal is that subsets of children with distinct infection risk are best captured through the proteome, which represents the composite inflammatory profile critical to infection response. This will be explored in a cohort of children with existing proteomic and metabolomic data and extensive longitudinal follow-up through age 10 YR, originally enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). (Aim 1) Proteomic profiling will be used as input to derive inflammatory subtypes (i.e.,“inflamma-types”) at age 1 YR using a discovery and validation approach; then, a high risk inflamma-type for respiratory infections will be identified. (Aim 2) Inflamma-types will be recapitulated at age 6 YR to investigate their stability across the spectrum of respiratory maturation and immune development. Finally, (Aim 3) inflamma-types will be characterized biochemically to identify key metabolites and key pathways through the metabolome and assess their roles as mediators in subsequent disease development (i.e., asthma). This innovative research plan utilizes novel methodologies and will represent the first study to derive proteomic-driven subtypes to understand respiratory infection risk. An accompanying training plan is designed to provide Dr. Prince support in completing these research aims successfully and facilitate her transition to independence. These findings will provide critical preliminary data to submit subsequent R01 applications to externally validate inflamma-types and assess their clinical utility. Dr. Prince has four career goals that build upon her existing reputation as a biochemist to (1) gain foundational knowledge in immunology and respiratory medicine; (2) increase clinical understanding of respiratory infections in early life; (3) strengthen her knowledge of multi-omics interpretation; and (4) deepen her understanding of study design, mentoring, and research ethics. She is supported by a mentoring team with diverse skill sets and successful me...