Date of Award

2023

Degree Name

Pharmaceutical Sciences

College

School of Pharmacy

Type of Degree

M.S.

Document Type

Thesis

First Advisor

Dr. Melinda E Varney, Committee Chairperson

Second Advisor

Dr. Jeremy McAleer, Committee Member

Third Advisor

Dr. Cynthia B Jones, Committee Member

Abstract

Among other disease outcomes, obesity is associated with 1) reduction in long-lasting immune protection and 2) acquisition of cancer. Given our interest in hematopoietic stem and progenitor cell (HSPC) dynamics, we questioned if similar mechanisms in the bone marrow microenvironment contribute to obesity-induced HSPC alterations responsible for 1) decreased immune protection and 2) transformation of HSPCs in the pathogenesis of hematologic malignancies. The negative effects of obesity on immune protection are most notably established in influenza models. Influenza infection susceptibility is increased and influenza vaccine-induced immunity wains in obese individuals. Ongoing studies aim to define mechanisms for waning immunity at sites of infection. Little is understood, however, regarding how obesity affects HSPC dynamics in the bone marrow microenvironment upon immunization. We hypothesized that obesity alters the types and quantities of immune cells produced by HSPCs upon immunization. We further hypothesized that this is due to altered availability of cytokines present in the bone marrow. Similarly, we hypothesized that unique cytokine signatures in the bone marrow of obese individuals serve as a mechanism for cancer initiation and progression in those with genetic susceptibility to MDS. To test our hypotheses, we subjected applicable mouse models to low-fat or high-fat diets. In our immunization studies, results indicate that high-fat diet leads to myeloid skewing in flu-immunized mice and that cytokine trends in the bone marrow provide insight into how this occurs. In our cancer studies, MDS-susceptible mice fed a high-fat diet displayed distinct cytokine signatures when compared to those fed a low-fat diet, suggesting that this may be a mechanism by which obesity contributes to hematologic malignancy. Further understanding of the contribution of obesity-induced bone marrow cytokine signatures to poor health outcomes may inform the design of future vaccine formulations or MDS therapeutics for obese patients.

Subject(s)

Diet – Health aspects.

Obesity – Cancer.

Obesity – Health aspects.

Bone marrow – Cytology.

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