PROJECT SUMMARY Chronic pain in pediatric sickle cell disease (SCD) is a major clinical challenge due to the complex interaction of biological, psychological, and social factors. Consequently, current pharmacological and non- pharmacological treatments have variable and limited effectiveness resulting in the persistence of chronic pain during adolescence into adulthood. Optimal treatment of chronic SCD pain requires an individualized, interdisciplinary care approach that targets the multifaceted biopsychosocial factors that maintain chronic pain, such as chronic inflammation, nervous system sensitization, stress, and emotional distress. The objective of the proposed research is to determine if there are measurable elevated proinflammatory biomarkers among youth with chronic SCD pain that are driven by stress, depression, and anxiety that can be targeted and modified through non-pharmacological treatment approaches, such as cognitive-behavioral therapy. The aims of the proposed study are to 1) determine if there are key inflammatory biomarkers associated with chronic SCD pain and stress, and 2) determine if inflammatory biomarkers change for youth with chronic SCD pain following an adaptive, family-focused, culturally-informed cognitive-behavioral intervention termed Back2Life that is tailored to address the unique needs of chronic pain in pediatric SCD. A 24-month retrospective longitudinal study will evaluate stored blood samples from youth with chronic SCD pain to determine the rates of elevated proinflammatory cytokines and their relationship to pain and stress. We will prospectively evaluate the trajectory of proinflammatory biomarkers among youth with chronic SCD pain participating in a proof-of- concept clinical trial of Back2Life to see if these markers change with treatment and inform preliminary effect sizes in order to prepare for a larger clinical trial. Our long-term goal is to develop novel comprehensive treatment approaches to treat chronic pain in pediatric SCD and improve quality of life.