Project Summary/Abstract Growth impairment is a common complication of pediatric Crohn’s disease. Normalization of growth is a marker of disease control and successful Crohn’s disease therapy. Treatment strategies for improving growth impairment and final adult height are currently suboptimal. The impact of Crohn’s disease on growth is potentially mediated by many factors, including inflammation, genetics, microbiome, nutrition, and medications. The continued presence of growth impairment primarily reflects continued suboptimal treatment of the underlying inflammation characteristic of Crohn’s disease. We hypothesize that the inflammation characteristic of Crohn’s disease has greater negative effects on endocrine growth regulators (IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater negative inflammatory effects help to explain the increased susceptibility to growth impairment in males. This hypothesis is based on our analyses of data collected from our completed prospective multicenter longitudinal study of sex differences in growth impairment (Growth Study Part 1). Our Part 1 data show that as bone age progresses, standardized height gain is lower in males. Our Part 1 findings suggest inflammation exerts a greater negative effect on hormone levels and growth in males, and indicate that sex-specific molecular pathways lead to growth impairment in children with Crohn’s disease. The primary pathway to growth impairment appears be the growth hormone/IGF-1 axis in males and the hypothalamic/pituitary/gonadal axis in females. Developing a sex-specific risk-based treatment approach for children with Crohn’s disease is essential. However, the specific molecular mechanisms causing sex differences in growth impairment remain poorly characterized. Here, we propose to expand and continue to follow our cohort to harvest information on the proteome (Aim 1) and genome (Aim 2) to provide new insights into growth impairment. These data will enhance our ability to determine the underlying mechanisms of sex differences in growth impairment (Aims 1 and 2) and develop robust sex-specific predictive models to identify high-risk patients (Aim 3). Part 2 of the Growth Study will generate essential data that will enable us to develop a highly needed sex-specific risk- based pediatric Crohn’s disease treatment approach, which will represent a major paradigm shift in clinical practice. Institution of appropriate personalized sex-specific risk-based medical therapies targeting the underlying inflammation (since improved growth results from improved disease control) is essential since only a very narrow therapeutic interval is available to intervene to improve growth before growth plates close.