Molecular Mechanism and Targeting of Chronic Pain in Sickle Cell Disease

Our long-term goal is to advance the knowledge of the molecular and neurobiological mechanisms underlying chronic pain in sickle cell disease (SCD) and develop effective pharmacologic treatments. Pain is not only a life-long companion but also a predictor of mortality for the 100,000 Americans, millions more worldwide living with SCD.1-3 Pain and SCD are so intimately intertwined, that African tribal words for the disease, spoken hundreds of years before Herrick described SCD in the western literature, are onomatopoeic for pain. Nationwide epidemiological survey data indicate that annually only 39% of patients with SCD have no pain episodes, 55% have 1- 2 episodes, 5% have 3 to 10 painful episodes, and 1% of patients have more than 10 episodes.1 Though it is now appreciated that SCD pain is characterized by chronic pain with episodes of acute pain crisis,4-5 the neurobiology of chronic pain is poorly studied, not well characterized, and is often refractory to currently available therapies,6-8 a century after Herrick’s seminal paper.9 A great deal of research has been carried on the disease itself. Several transgenic models of SCD have been developed, including the humanized Berkeley (BERK) and Townes’ sickle cell transgenic mice (TOW), both representing SCD phenotypes that closely mimics many features of severe SCD in humans. We propose to employ these well- characterized sickle cell transgenic mouse models for studying epigenetic (microRNA), neurobiology (tyrosine hydroxylase), and gut microbiota mechanisms underlying chronic pain, which can hold much promise for a more thorough understanding of pain mechanisms in SCD and may guide the development of effective therapies. Our research applies the power of molecular and cellular biology, pharmacology, neurobiology, epigenetics, targeted drug delivery, and other cutting-edge tools, and we have ongoing research, existing expertise and research capacity for studying chronic sickle pain problems using the multipronged complementary approaches. Moreover, this R35 program is designed to have flexibility so that new research directions can be rapidly taken when new findings or emerging technologies become available. Our innovation has a high probability of success given our outstanding track record, vibrant ongoing research program, and the designed flexibility in pursuing new research directions. Having moved a drug candidate from bench to a Phase I study in patients with SCD, our team is uniquely suited to carry out future translation research to benefit the patients with SCD.