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Sickle cell disease (SCD) is the most common group of genetic, chronic hematologic disorders, and is characterized by chronic pain resulting from vaso-occlusive episodes. As such, youth with SCD utilize a disproportionately high amount of health care resources. Youth with frequent health care utilization (HCU) are at increased risk for psychosocial consequences, including disruptions in family functioning and decreased academic performance. While studies have separately examined HCU, family functioning, and academic achievement in this population, there is a dearth of research examining the association between these variables. The present study aimed to: (1) examine associations between family environment and patterns of HCU, (2) examine associations between patterns of HCU and academic achievement scores in math and reading, and (3) evaluate the indirect effect of family environment on academic achievement scores in math, as explained by patterns of HCU. This study included 41 youth with HbSS or HbS beta-thalassemia. Youth were administered the Woodcock-Johnson III Achievement, and caregivers completed the Family Environment Scale. Sociodemographic characteristics were collected, and medical history information was obtained via retrospective medical chart review. Overall, participants reported a more positive family environment, demonstrated less pain-related ED visits and hospital admissions, and obtained below average scores on academic achievement in math and reading. The present study did not provide evidence of associations between family environment, HCU, and academic achievement. Unique characteristics of the study sample, as well as clinical implications and next steps for future research are discussed.

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Sickle cell anemia, caused by a point mutation that affects the HBB gene, is one of the most common human genetic disorders world-wide and has a high morbidity and mortality. A single FDA approved drug, hydroxyurea, is available for its ability to induce fetal hemoglobin expression, a major modulator of disease severity. Not every patient responds to treatment and additional HbF-inducing drugs are needed. In this thesis, I outline an induced pluripotent stem cell-based approach to the study of sickle cell disease (SCD). In the lab, we are currently building a library of SCD-induced pluripotent stem cell (iPSC) lines from a cohort of SCD patients with different genetic backgrounds and fetal hemoglobin levels. Utilizing a directed-differentiation approach, iPSC can give rise to hematopoietic progenitors that are similar to megakaryocyte-erythroid progenitors and can be further specified to become cells of either lineage. I examined the hypothesis that an iPSC-based system would be capable of producing fully functional erythroid cells and also recapitulate the variation in fetal hemoglobin levels seen in SCD patients. Directed-differentiation of iPSCs produced erythroid-lineage cells that were responsive to oxygen levels and erythropoietin, and were capable of further maturation and increased hemoglobin production. A humanized mouse model demonstrated the ability of these cells to localize to the bone marrow, contribute to the peripheral blood, and survive in vivo for over two weeks. The maturation capability of SCD-specific iPSC-derived erythroid lineage cells was correlated with hemoglobin expression and compared to control cells. Characterization of in vitro and in vivo differences between control and SCD-specific iPSC-derived erythroid-lineage cells demonstrated variation amongst individuals, similar to the variation seen in patients. Both of these patient-specific iPSC-based in vitro and in vivo models allow for the examination of the effect of genetic variability on fetal hemoglobin expression and also for the modeling of patient-specific responses to drug treatment. This information will facilitate better clinical treatment of the disease.

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This study helps to fill a remaining knowledge gap surrounding the mechanisms and pathways that contribute to cardiomyopathies in SCD. A better understanding of the pathophysiological mechanisms could lead to more accurate therapeutic targets to improve quality of life as well as life expectancy. In this study I recapitulate cardiac dysfunction in vitro by exposing engineered mouse cardiac tissues to ANG II or the sickled microenvironment. Experimental results include gene expression profiles and oxidative stress generation. Gene expression profiles in the ANG II treated tissues indicated a pathological state with upregulation in biomarkers for inflammation, cell adhesion, wall stress and ECM related genes. Further research is being conducted using insights gained from this study which will lead to a broader understanding of the biological processes involved and potentially identify novel therapeutic targets that may ultimately improve patient outcomes.

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