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Item Human Neural Stem Cells in Space Proliferate more than Ground Control Cells: Implications for Long-Term Space Travel(Herald, 2021-04) Shaka, Sophia; Carpo, Nicholas; Tran, Victoria; Ma, Yao-Ying; Karouia, Fathi; Espinosa-Jeffrey, Araceli; Pharmacology and Toxicology, School of MedicineLong-term travel and lengthy stays for astronauts in outer space are imminent. To date, more than 500 astronauts have experienced the extreme conditions of space flight including microgravity and radiation. For the past decade, many studies associated with long-duration spaceflight have shown the recurring occurrence of ophthalmic abnormalities. The reasons of the observed changes in some astronauts remained unclear. However, factors such as the increase in intracranial pressure and fluid shifts are among the top potential contributing elements. Here we report a study that specifically looked at the effect of space environment on the proliferation and physiology of human Neural Stem Cells (NSCs) onboard the International Space Station (ISS) as compared to ground controls. The study revealed that human NSCs proliferated seven times more while in space (SPC) when compared to on Earth (1G) control cultures. We also examined by continuous live imaging the behavior of space flown NSCs upon return to Earth. We found that after space flight, they continued proliferating at the same pace as 1G controls. Interestingly, NSCs flown to space displayed a larger diameter than control cells. These phenomena, increased proliferation while in space and larger cell soma may contribute to intracranial hypertension found in astronauts, representing a risk factor and potential limitation to long duration space missions such as travelling to the Moon or Mars. In addition, NSCs are essential to maintain Central Nervous System (CNS) function, as they are the basis for the regeneration of CNS cell populations in health and disease.Item Loss of inversin contributes to renal cystic disease through altered cellular processes and decreased sodium transport in renal epithelial cells(2017-05) Kulkarni, Nalini H.; Blazer-Yost, Bonnie L.Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys. Increased kidney size in NPHP2 may involve altered cell growth, apoptosis, electrolyte transport and fluid accumulation in the cysts. To test this hypothesis, histology and transcriptome analysis were performed on one-day old wild-type and inv/inv mice to uncover molecular pathways altered in the mutant mice. Histology of inv/inv mice kidneys showed dilated cystic tubules compared to wild type. Pathway analysis of transcriptome data showed that inversin exerts its effects on kidneys, at least in part, through the transcriptional regulation of genes implicated in inflammation, immune response, cellular metabolism, cell cycle and ion transport. Genes involved in inflammation or immune response were upregulated whereas the genes involved in cell cycle progression and ion transport were downregulated. To validate the array findings from inv/inv mice kidneys, functional consequence of inversin loss on transepithelial ion transport was measured by electrophysiological techniques in shRNA mediated inversin-depleted renal cell type isolated from mouse cortical collecting duct (mCCD). Depletion of inversin decreased vasopressin-induced Na+ absorption, but did not alter Cl- secretion in mCCD cells. Addition of amiloride, a specific blocker of the epithelial sodium channel (ENaC), abolished basal ion transport in both inversin knockdown and control cells indicating ENaC involvement. Loss of inversin decreased Na+ absorption and this effect, in part, was mediated by transcriptional and post-translational regulation of ENaC mediators. To better understand inversin function in renal cells, transcriptome analysis was performed in control and inversin-depleted mCCD cells. Pathway analysis showed that inversin-depletion altered the genes represented in cell cycle, cellular assembly and organization, DNA replication, cell proliferation and ion transport in this isolated renal cell type. In concordance with the array data from inv/inv mice kidneys, a decrease in the expression of cell cycle, ion transport and apoptotic genes were observed accompanied by an upregulation of genes implicated in inflammatory or immune response indicating a direct effect of inversin on renal cells. Together, this study utilized a combination of transcriptome and functional analyses to unravel the role of inversin in renal cells. These data demonstrate that loss of inversin can cause a delay in cell cycle progression with a decrease in cell proliferation and apoptosis which in turn can perturb the development of the renal tubule. Also, a decrease in Na+ reabsorption together with differential regulation of other ion transporters can result in altered electrolyte transport contributing to cystogenesis, cyst growth, fluid accumulation and cyst expansion in NPHP2.Item Nrf2 Deficiency Augments the Activity of Hepatic Progenitor Cells during Cholestasis(Office of the Vice Chancellor for Research, 2013-04-05) Wang, Guo-Ying; Zou, Yuhong; Dai, GuoliTranscription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular defense against oxidative stress and inflammation and is also involved in regulating liver regeneration. The aim of the study is to evaluate whether Nrf2 mediates hepatic repair response during cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation or sham operation. Various assessments were performed at 5, 10, 15, 25, and 40 days following surgery. Significant genotype-dependent differences in liver injury, cell proliferation, and collagen deposition were not seen over the time course of the study, in line with several reports. However, Nrf2-null mice exhibited a more prominent network of septual tissue containing laminin and α-fetal protein expressing cells at 15 days after injury, suggesting a stronger repair response, than their wild-type litter mates. In the livers of both genotypes of mice, cytokeratin 19 (CK19), a marker of bipotent liver epithelial progenitors and immature billiary epithelial cells, were expressed in the epithelial cells of newly formed bile ducts and a population of hepatocytic-appearing cells in parenchyma. Notably, Nrf2-null mice showed higher hepatic protein expression of CK19 at 5 days following BDL, indicating earlier onset of the activation of CK19+ progenitor cells, than wild-types. CD133, a marker of liver progenitors, were found to be expressed by newly generated bile duct epithelial cells and a population of hepatocytic-appearing parenchymal cells in the livers of the two genotypes of mice. Hepatic CD133 protein expression was gradually elevated, paralleling continuous increase in the number of CD133+ hepatocytic-appearing cells, as the cholestasis progressed. Remarkably, the lack of Nrf2 led to markedly higher magnitudes of the increases in hepatic CD133 protein level and in the number of CD133+ hepatocytic-appearing cells. Collectively, our data demonstrate that Nrf2 deficiency evokes higher activity of liver progenitor cells and thus stronger liver repair response. The findings indicate that Nrf2 is an important regulator of the activity of hepatic progenitor/stem cells during chronic liver injury.Item Targeting the Role of Tyrosine in Amot Protein-lipid Binding Events(Office of the Vice Chancellor for Research, 2015-04-17) Abufares, Nawara A.; Kimble-Hill, Ann C.Amot proteins have been shown to control cell proliferation and differentiation and can selectively bind with high affinity to phosphoinositol containing membranes. This binding event is linked to endocytosis, changes in cellular polarity, and apical membrane sequestration of nuclear transcription factors associated with development of cancer phenotypes. Although the lipid selectivity of the protein has been well characterized, the mechanisms involved in the Amot coiled-coil homology domain (ACCH) binding these membranes are not yet known. The fluorescence properties of the ACCH domain were used to characterize the binding event, however it became clear each of the five native tyrosines proximity to membrane might differ based on fluorescence resonance energy transfer experiments with fluorescently tagged lipids. A variety of short peptides correlating to the amino acid sequence of Amot surrounding these tyrosines were assayed and observed in different membrane mimicking environments to determine if each tyrosine had the ability to bury into the hydrophobic region of the membrane (alcohol study), or simply interacted with the hydrophilic head groups (liposome study). Interactions were characterized by shifts in absorbance, excitation and emission scans peaks. A characterization of these shifts with respect to what is seen with the various tyrosine-phenalanine mutants will further our understanding of whether each tyrosine is buried within the protein or interacts with the membrane. Mentor: Ann Kimble-Hill, Department of Biochemistry, IU School of Medicine