Knisely Submits Proposal on Sickle Cell Disease

Knisely Submits Proposal on Sickle Cell Disease

mitch kniselyGood news! Kudos to Mitch Knisely, assistant professor, and Allison Ashley-Koch of Duke Molecular Physiology Institute and their entire team for the submission of their NIH R21 application entitled: "Epigenetic Age Acceleration and Psychoneurological Symptoms in Sickle Cell Disease." This proposal requests funding for a two-year period with a start date of September 1, 2021.

Individuals with sickle cell disease (SCD) experience deleterious psychoneurological symptoms, such as pain, sleep disturbances, depressive symptoms, and cognitive impairment. Among these symptoms, there is notable interindividual variability in symptomatology. However, there is a limited understanding why some individuals experience worse psychoneurological symptoms than others.

Identifying the biological factors, such as epigenetic mechanisms, that influence the variability of symptom experiences in SCD can help inform the development of risk assessment tools and interventions that promote health maintenance and quality of life. Several lines of converging evidence suggests a person’s epigenetic age may be associated with psychoneurological symptom experiences in SCD. Epigenetic age is calculated by assessing DNA methylation patterns at numerous CpG loci that account for the pace of cellular aging or declining tissue function. Premature epigenetic age acceleration putatively involves many physiologic processes, including increased inflammation, oxidative stress, and mitochondrial dysfunction, and more recently, investigators have begun to identify associations with epigenetic age acceleration and psychoneurological symptom experiences in other chronic disease populations. However, whether epigenetic age acceleration occurs and if it is associated with these symptoms in individuals with SCD remains unknown.

The specific aims of this cross-sectional study are to 1) characterize epigenetic aging DNA methylation patterns and determine presence of epigenetic age acceleration and 2) identify associations between epigenetic age acceleration and psychoneurological symptoms (pain, sleep disturbances, depressive symptoms, and cognitive function) in adults with SCD.

DNA samples and patient-reported outcome data collected at Duke University as part of the Sickle Cell Disease Consortium Research Registry (n=92) will be used in this study. DNA methylation data will be generated from extracted DNA from blood specimens and used to calculate epigenetic age. Because different epigenetic clocks provide different measures and characteristics of epigenetic aging, epigenetic age acceleration will be calculated using three epigenetic clocks (Horvath, Hannum, and Levine epigenetic clocks). We will also examine whether the calculations from each of the clocks are correlated in the sample. Patient-reported data for each symptom of interest existing in the SCDIC Registry will be used to determine associations with epigenetic age acceleration for each of the epigenetic clocks. Multiple regression models for each symptom outcome will be built, including accelerated aging as the key covariate, and controlling for other potential confounding variables (e.g., cell type heterogeneity, demographics, and other clinical characteristics).

The potential payoff of this study is high as our approach may provide novel insight into epigenetic aging biomarkers associated with symptom development and health outcomes in people with SCD. Thank you to all those who gave their time and expertise in guiding the application process as well as to all those who helped to prepare for this submission.

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