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Item Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids(Elsevier, 2019-07-09) Tang, Pei-Ciao; Alex, Alpha L.; Nie, Jing; Lee, Jiyoon; Roth, Adam A.; Booth, Kevin T.; Koehler, Karl R.; Hashino, Eri; Nelson, Rick F.; Otolaryngology, IU School of MedicineMutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequencing to investigate the role of TMPRSS3. Defective Tmprss3 leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells demonstrate reduced numbers of BK channels and lower expressions of genes encoding calcium ion-binding proteins, suggesting a disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to ER of cells in inner ear organoids. Our in vitro model recapitulated salient features of genetically associated inner ear abnormalities and will serve as a powerful tool for studying inner ear disorders.Item Differentiation and characterization of cell types associated with retinal degenerative diseases using human induced pluripotent stem cells(2014-07-31) Gupta, Manav; Meyer, Jason S.; Belecky-Adams, Teri; Randall, Stephen Karl, 1953-Human induced pluripotent stem (iPS) cells have the unique ability to differentiate into 200 or so somatic cell types that make up the adult human being. The use of human iPS cells to study development and disease is a highly exciting and interdependent field that holds great promise in understanding and elucidating mechanisms behind cellular differentiation with future applications in drug screening and cell replacement studies for complex and currently incurable cellular degenerative disorders. The recent advent of iPS cell technology allows for the generation of patient-specific cell lines that enable us to model the progression of a disease phenotype in a human in vitro model. Differentiation of iPS cells toward the affected cell type provides an unlimited source of diseased cells for examination, and to further study the developmental progression of the disease in vitro, also called the “disease-in-a-dish” model. In this study, efforts were undertaken to recapitulate the differentiation of distinct retinal cell affected in two highly prevalent retinal diseases, Usher syndrome and glaucoma. Using a line of Type III Usher Syndrome patient derived iPS cells efforts were undertaken to develop such an approach as an effective in vitro model for studies of Usher Syndrome, the most commonly inherited disorder affecting both vision and hearing. Using existing lines of iPS cells, studies were also aimed at differentiation and characterization of the more complex retinal cell types, retinal ganglion cells (RGCs) and astrocytes, the cell types affected in glaucoma, a severe neurodegenerative disease of the retina leading to eventual irreversible blindness. Using a previously described protocol, the iPS cells were directed to differentiate toward a retinal fate through a step-wise process that proceeds through all of the major stages of neuroretinal development. The differentiation process was monitored for a period of 70 days for the differentiation of retinal cell types and 150 days for astrocyte development. The different stages of differentiation and the individually derived somatic cell types were characterized by the expression of developmentally associated transcription factors specific to each cell type. Further approaches were undertaken to characterize the morphological differences between RGCs and other neuroretinal cell types derived in the process. The results of this study successfully demonstrated that Usher syndrome patient derived iPS cells differentiated to the affected photoreceptors of Usher syndrome along with other mature retinal cell types, chronologically analogous to the development of the cell types in a mature human retina. This study also established a robust method for the in vitro derivation of RGCs and astrocytes from human iPS cells and provided novel methodologies and evidence to characterize these individual somatic cell types. Overall, this study provides a unique insight into the application of human pluripotent stem cell biology by establishing a novel platform for future studies of in vitro disease modeling of the retinal degenerative diseases: Usher syndrome and glaucoma. In downstream applications of this study, the disease relevant cell types derived from human iPS cells can be used as tools to further study disease progression, drug screening and cell replacement strategies.Item Gray matter density loss in essential tremor: a lobule by lobule analysis of the cerebellum(BMC, 2017-07-03) Dyke, Jonathan P.; Cameron, Eric; Hernandez, Nora; Dydak, Ulrike; Louis, Elan D.; Radiology and Imaging Sciences, School of MedicineBACKGROUND: The pathophysiological basis for essential tremor (ET) remains unclear, although evidence increasingly links it to a disordered and perhaps degenerative cerebellum. Prior imaging studies have treated the cerebellum en bloc. Our hypothesis was that regional differences in cerebellar gray matter (GM) density may better distinguish ET cases from controls. Forty-seven ET cases and 36 control subjects were imaged using magnetic resonance imaging (MRI). The cerebellum was segmented into 34 lobes using a Spatially Unbiased Infra-Tentorial Template (SUIT) atlas within the Statistical Parametric Mapping (SPM) analysis package. Age, gender and Montreal Cognitive Assessment (MoCA) scores were regressed out from the statistical models to isolate group effects. ET cases were further stratified into phenotypically-defined subgroups. The Benjamini-Hochberg False Discovery Rate procedure (BH FDR) (α = 0.1) was used to correct for multiple comparisons. RESULTS: When all ET cases and controls were compared, none of the regions met the BH FDR criteria for significance. When compared with controls, ET cases with head or jaw tremor (n = 27) had significant changes in GM density in nine cerebellar lobules, with a majority in the left cerebellar region, and each meeting the BH FDR criteria. Likewise, ET cases with voice tremor (n = 22) exhibited significant changes in 11 lobules in both left and right regions and the vermis. These analyses, in sum, indicated decreases in GM density in lobules I-IV, V, VI, VII and VIII as well as the vermis. ET cases with severe tremor (n = 20) did not show regions of change that survived the BH FDR procedure when compared to controls. CONCLUSIONS: We showed that ET cases with various forms of cranial tremor differed from controls with respect to cerebellar GM density, with evidence of GM reduction across multiple cerebellar regions. Additional work, using a lobule-by-lobule approach, is needed to confirm these results and precisely map the regional differences in ET cases, subgroups of ET cases, and controls.Item Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells: Applications for the Study and Treatment of Optic Neuropathies(Springer, 2015-09) Cooke, Jessica A.; Meyer, Jason S.; Department of Biology, School of ScienceItem Nam Family, a study in cacogenics(Cold Spring Harbor, 1912-01-01) Estabrook, ArthurItem Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia(Cell Press, 2021) Huang, Ning; Li, Sunan; Xie, Yuxiang; Han, Qi; Xu, Xiao-Ming; Sheng, Zu-Hang; Neurological Surgery, School of MedicineMitochondria supply adenosine triphosphate (ATP) essential for neuronal survival and regeneration. Brain injury and ischemia trigger acute mitochondrial damage and a local energy crisis, leading to degeneration. Boosting local ATP supply in injured axons is thus critical to meet increased energy demand during nerve repair and regeneration in adult brains, where mitochondria remain largely stationary. Here, we elucidate an intrinsic energetic repair signaling axis that boosts axonal energy supply by reprogramming mitochondrial trafficking and anchoring in response to acute injury-ischemic stress in mature neurons and adult brains. P21-activated kinase 5 (PAK5) is a brain mitochondrial kinase with declined expression in mature neurons. PAK5 synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 signaling remobilizes and replaces damaged mitochondria via the phosphorylation switch that turns off the axonal mitochondrial anchor syntaphilin. Injury-ischemic insults trigger AKT growth signaling that activates PAK5 and boosts local energy supply, thus protecting axon survival and facilitating regeneration in in vitro and in vivo models. Our study reveals an axonal mitochondrial signaling axis that responds to injury and ischemia by remobilizing damaged mitochondria for replacement, thereby maintaining local energy supply to support central nervous system (CNS) survival and regeneration.Item The Role of 7,8-Dihydroxyflavone in Preventing Dendrite Degeneration in Cortex After Moderate Traumatic Brain Injury(Springer, 2016-04) Zhao, Shu; Gao, Xiang; Dong, Weiren; Chen, Jinhui; Department of Neurological Surgery, IU School of MedicineOur previous research showed that traumatic brain injury (TBI) induced by controlled cortical impact (CCI) not only causes massive cell death, but also results in extensive dendrite degeneration in those spared neurons in the cortex. Cell death and dendrite degeneration in the cortex may contribute to persistent cognitive, sensory, and motor dysfunction. There is still no approach available to prevent cells from death and dendrites from degeneration following TBI. When we treated the animals with a small molecule, 7,8-dihydroxyflavone (DHF) that mimics the function of brain-derived neurotrophic factor (BDNF) through provoking TrkB activation reduced dendrite swellings in the cortex. DHF treatment also prevented dendritic spine loss after TBI. Functional analysis showed that DHF improved rotarod performance on the third day after surgery. These results suggest that although DHF treatment did not significantly reduced neuron death, it prevented dendrites from degenerating and protected dendritic spines against TBI insult. Consequently, DHF can partially improve the behavior outcomes after TBI.Item Some Families as Factors in Anti-Social Conditions(Baltimore: Williams & Wilkins Co., 1923) Butler, Amos W.Item The Sterilization of Degenerates(2007-06-18T16:47:48Z) Sharp, Harry