PhD Grad: Melanie R. Shapiro

Mentors: Dr. Todd Brusko and Dr. Mark Atkinson

Dr. Melanie Shapiro is, without question, one of the most – if not the most – talented young scientists we have ever encountered throughout our combined 35 years as principal investigators. Her knowledge of and dedication to type 1 diabetes research far exceeds expectations.  Indeed, Melanie’s technical skill sets and research productivity are unsurpassed. Melanie hypothesized that the two insulin-like growth factors (IGFs), IGF1 and IGF2, or their bioavailability, regulated by seven IGF binding proteins (IGFBP), are altered during development of the autoimmune disease, type 1 diabetes, potentially by modulating immune cell proliferation and function. Indeed, Melanie’s careful and thorough investigation revealed that IGF levels are dysregulated prior to and following clinical diagnosis of type 1 diabetes, supporting further efforts to evaluate their use as disease predictive biomarkers. She also demonstrated that IGF1 signaling synergizes with the cytokine IL-2 to preferentially promote the expansion of naïve regulatory T cells (known as Tregs), which are critical for the maintenance of immunological tolerance and prevention of type 1 diabetes. She uncovered IGF1 receptor (IGF1R) expression levels as the mechanism underlying this relationship with naïve Tregs expressing higher levels of IGF1R than other T cell subsets. Importantly, she characterized the immunological impact of a novel genetic mutation affecting IGF1R, with multiple members of one family carrying the mutation exhibiting growth impairments and low blood sugar. Finally, she carried out essential work characterizing the immune profile and type 1 diabetes development in a novel line of CD226 knockout non-obese diabetic (NOD) mice. She demonstrated that CD226 knockout NOD mice had decreased disease incidence and insulitis as compared to controls. Moreover, CD226 knockout T cells were less capable of transferring autoimmune diabetes. Of note, CD226 knockout mice demonstrated increased numbers of CD8+ single positive thymus cells, leading to increased numbers of CD8+ T cells in the spleen. Decreased percentages of memory T cells were observed in the pancreatic lymph nodes of CD226 knockout mice. Her data support a role for CD226 in type 1 diabetes development by modulating thymic T cell selection and impacting peripheral memory/effector CD8+ T cell activation and function. Throughout the course of her graduate career, Melanie’s predoctoral fellowship has been supported by an NIH F31 grant as well as funding through the Children’s Miracle Network. She has been first-author on two peer-reviewed publications and co-author on three additional manuscripts. We are glad that Dr. Shapiro will be continuing on as a post-doctoral fellow in Dr. Todd Brusko’s lab within the UF Diabetes Institute.