Assessing teen risk behavior and later drug use

Gemstone Team Risky Business

The role of intracellular calcium perturbations in muscle damage and dysfunction in mouse models of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. DMD is clinically characterized by severe, progressive and irreversible loss of muscle function, in which most patients lose the ability to walk by their early teens and die by their early 20’s. Impaired intracellular calcium (Ca2+) regulation and activation of cell degradation pathways have been proposed as key contributors to DMD disease progression. This dissertation research consists of three studies investigating the role of intracellular Ca2+ in skeletal muscle dysfunction in different mouse models of DMD. Study one evaluated the role of Ca2+-activated enzymes (proteases) that activate protein degradation in excitation-contraction (E-C) coupling failure following repeated contractions in mdx and dystrophin-utrophin null (mdx/utr-/-) mice. Single muscle fibers from mdx/utr-/- mice had greater E-C coupling failure following repeated contractions compared to fibers from mdx mice. Moreover, protease inhibition during these contractions was sufficient to attenuate E-C coupling failure in muscle fibers from both mdx and mdx/utr-/- mice. Study two evaluated the effects of overexpressing the Ca2+ buffering protein sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) in skeletal muscles from mdx and mdx/utr-/- mice. Overall, SERCA1 overexpression decreased muscle damage and protected the muscle from contraction-induced injury in mdx and mdx/utr-/- mice. In study three, the cellular mechanisms underlying the beneficial effects of SERCA1 overexpression in mdx and mdx/utr-/- mice were investigated. SERCA1 overexpression attenuated calpain activation in mdx muscle only, while partially attenuating the degradation of the calpain target desmin in mdx/utr-/- mice. Additionally, SERCA1 overexpression decreased the SERCA-inhibitory protein sarcolipin in mdx muscle but did not alter levels of Ca2+ regulatory proteins (parvalbumin and calsequestrin) in either dystrophic model. Lastly, SERCA1 overexpression blunted the increase in endoplasmic reticulum stress markers Grp78/BiP in mdx mice and C/EBP homologous protein (CHOP) in mdx and mdx/utr-/- mice. Overall, findings from the studies presented in this dissertation provide new insight into the role of Ca2+ in muscle dysfunction and damage in different dystrophic mouse models. Further, these findings support the overall strategy for improving intracellular Ca2+ control for the development of novel therapies for DMD.

Playing for Real: Designing Alternate Reality Games in Learning Contexts

Alternate Reality Game (ARG) represent a new genre of transmedia practice where players hunt for scattered clues, make sense of disparate information, and solve puzzles to advance an ever-evolving storyline. Players participate in ARGs using multiple communications technologies, ranging from print materials to mobile devices. However, many interaction design challenges must be addressed to weave these everyday communication tools together into an immersive, participatory experience. Transmedia design is not an everyday process. Designers must create and connect story bits across multiple media (video, audio, text) and multiple platforms (phones, computers, physical spaces). Furthermore, they must engage with players of varying skill levels. Few studies to-date have explored the design process of ARGs in learning contexts. Fewer still have focused on challenges involved in designing for youth (13-17 years old). In this study, I explore the process of designing ARGs as vehicles for promoting information literacy and participatory culture for adolescents (13-17 years old). Two ARG design scenarios, distinguished by target learning environment (formal and informal context) and target audience (adolescents), comprise the two cases that I examine. Through my analysis of these two design cases, I articulate several unique challenges faced by designers who create interactive, transmedia stories for – and with – youth. Drawing from these design challenges, I derive a repertoire of design strategies that future designers and researchers may use to create and implement ARGs for teens in learning contexts. In particular, I propose a narrative design framework that allows for the categorization of ARGs as storytelling constructs that lie along a continuum of participation and interaction. The framework can serve as an analytic tool for researchers and a guide for designers. In addition, I establish a framework of social roles that designers may employ to craft transmedia narratives before live launch and to promote and scaffold player participation after play begins. Overall, the contributions of my study include theoretical insights that may advance our understanding of narrative design and analysis as well as more practical design implications for designers and practitioners seeking to incorporate transmedia features into learning experiences that target youth.