Applying Mathematical Models to Study the Role of the Immune System in Chronic Myelogenous Leukemia

Although tyrosine kinase inhibitors (TKIs) such as imatinib have transformed chronic myelogenous leukemia (CML) into a chronic condition, these therapies are not curative in the majority of cases. Most patients must continue TKI therapy indefinitely, a requirement that is both expensive and that compromises a patient's quality of life. While TKIs are known to reduce leukemic cells' proliferative capacity and to induce apoptosis, their effects on leukemic stem cells, the immune system, and the microenvironment are not fully understood. A more complete understanding of their global therapeutic effects would help us to identify any limitations of TKI monotherapy and to address these issues through novel combination therapies. Mathematical models are a complementary tool to experimental and clinical data that can provide valuable insights into the underlying mechanisms of TKI therapy. Previous modeling efforts have focused on CML patients who show biphasic and triphasic exponential declines in BCR-ABL ratio during therapy. However, our patient data indicates that many patients treated with TKIs show fluctuations in BCR-ABL ratio yet are able to achieve durable remissions. To investigate these fluctuations, we construct a mathematical model that integrates CML with a patient's autologous immune response to the disease. In our model, we define an immune window, which is an intermediate range of leukemic concentrations that lead to an effective immune response against CML. While small leukemic concentrations provide insufficient stimulus, large leukemic concentrations actively suppress a patient's immune system, thus limiting it's ability to respond. Our patient data and modeling results suggest that at diagnosis, a patient's high leukemic concentration is able to suppress their immune system. TKI therapy drives the leukemic population into the immune window, allowing the patient's immune cells to expand and eventually mount an efficient response against the residual CML. This response drives the leukemic population below the immune window, causing the immune population to contract and allowing the leukemia to partially recover. The leukemia eventually reenters the immune window, thus stimulating a sequence of weaker immune responses as the two populations approach equilibrium. We hypothesize that a patient's autologous immune response to CML may explain the fluctuations in BCR-ABL ratio that are regularly seen during TKI therapy. These fluctuations may serve as a signature of a patient's individual immune response to CML. By applying our modeling framework to patient data, we are able to construct an immune profile that can then be used to propose patient-specific combination therapies aimed at further reducing a patient's leukemic burden. Our characterization of a patient's anti-leukemia immune response may be especially valuable in the study of drug resistance, treatment cessation, and combination therapy.

Influence of Acute and Chronic Exercise on Markers of Hippocampal Plasticity

Exercise and physical activity are lifestyle behaviors associated with enriched mental health. Understanding the mechanisms by which exercise and physical activity improve mental health may provide insight for novel therapeutic approaches for numerous mental health disorders. This dissertation reports the findings from three studies investigating the influence of acute and chronic exercise on behavioral and mechanistic markers of hippocampal plasticity and delves into the potential role of noradrenergic signaling in the hippocampal adaptations with exercise. The first study assessed the effects of long-term voluntary wheel running on hippocampal expression of plasticity-associated genes and proteins in adult male and female C57BL/6J mice, highlighting sex differences in the adaptations to long-term voluntary wheel running. The second study examined the influence of acute exercise intensity on AMPA receptor phosphorylation, a mechanism essential for hippocampal plasticity, plasticity- associated gene expression, spatial learning and memory, and anxiety-like behavior. The unexpected finding that acute exercise increased anxiety-like behavior encouraged investigation into the role of central noradrenergic signaling in acute exercise-induced anxiety. The third study determined how previous exposure to voluntary wheel running modulates the response to an acute bout of exercise, focusing primarily on transcription of the important plasticity-promoting gene, brain-derived neurotrophic factor. Using a pharmacological approach to compromise the locus coeruleus noradrenergic system, a system that is implicated in age-related mental health disorders such as Alzheimer’s Disease, the third study also investigated the influence and interaction of the noradrenergic system and acute exercise on expression of multiple brain-derived neurotrophic factor transcripts. Together, this dissertation reports the findings from a series of experiments that explored similarities, differences, and interactions between the effects of acute and chronic exercise on markers of hippocampal plasticity and behavior. Further, this work provides insight into the role of the noradrenergic system in exercise-induced hippocampal plasticity.