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- All Subjects: RASopathies
- Creators: Hilbert, Alexander Robert
- Creators: Olson, Loren
Description
As the application of interactive media systems expands to address broader problems in health, education and creative practice, they fall within a higher dimensional space for which it is inherently more complex to design. In response to this need an emerging area of interactive system design, referred to as experiential media systems, applies hybrid knowledge synthesized across multiple disciplines to address challenges relevant to daily experience. Interactive neurorehabilitation (INR) aims to enhance functional movement therapy by integrating detailed motion capture with interactive feedback in a manner that facilitates engagement and sensorimotor learning for those who have suffered neurologic injury. While INR shows great promise to advance the current state of therapies, a cohesive media design methodology for INR is missing due to the present lack of substantial evidence within the field. Using an experiential media based approach to draw knowledge from external disciplines, this dissertation proposes a compositional framework for authoring visual media for INR systems across contexts and applications within upper extremity stroke rehabilitation. The compositional framework is applied across systems for supervised training, unsupervised training, and assisted reflection, which reflect the collective work of the Adaptive Mixed Reality Rehabilitation (AMRR) Team at Arizona State University, of which the author is a member. Formal structures and a methodology for applying them are described in detail for the visual media environments designed by the author. Data collected from studies conducted by the AMRR team to evaluate these systems in both supervised and unsupervised training contexts is also discussed in terms of the extent to which the application of the compositional framework is supported and which aspects require further investigation. The potential broader implications of the proposed compositional framework and methodology are the dissemination of interdisciplinary information to accelerate the informed development of INR applications and to demonstrate the potential benefit of generalizing integrative approaches, merging arts and science based knowledge, for other complex problems related to embodied learning.
ContributorsLehrer, Nicole (Author) / Rikakis, Thanassis (Committee member) / Olson, Loren (Committee member) / Wolf, Steven L. (Committee member) / Turaga, Pavan (Committee member) / Arizona State University (Publisher)
Created2014
Description
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.
ContributorsRoose, Cassandra Ann (Author) / Newbern, Jason M. (Thesis director) / Olive, Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05