Browsing by Author "Tutrow, Kaylee"
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Item A human induced pluripotent stem cell model of Alzheimer’s Disease‐associated fractalkine receptor polymorphism to assess AD‐related microglial dysfunction(Wiley, 2025-01-03) Tutrow, Kaylee; Harkin, Jade; Hernandez, Melody; Huang, Kang-Chieh S.; Bissel, Stephanie J.; Puntambekar, Shweta S.; Lamb, Bruce T.; Meyer, Jason S.; Medical and Molecular Genetics, School of MedicineBackground: Dysfunctional microglial activity has recently been identified as a potential mechanism leading to accumulation of amyloid beta and pTau and subsequent neurodegeneration in Alzheimer’s Disease. The CX3CR1/fractalkine axis serves as a mechanism for bi‐directional communication between microglia and neurons, respectively, to promote a resting, anti‐inflammatory state in microglia. Previous studies have demonstrated that deficiency in CX3CR1 signaling leads microglia to a more pro‐inflammatory phenotype, phagocytic deficits, and increased susceptibility of neurons to cell death. Additionally, the CX3CR1‐V249I polymorphism was recently identified as a potential risk allele for Alzheimer’s Disease with worsened Braak staging in post‐mortem Alzheimer’s patients. However, the role of fractalkine dysfunction in human cells and the mechanisms by which microglia with the CX3CR1‐V249I SNP contribute to neurodegeneration remain unclear. Method: To address this shortcoming, we utilized human induced pluripotent stem cells and CRISPR/Cas9 gene editing technology to elucidate the effects of the CX3CR1‐V249I polymorphism on human microglia‐like cells (hMGLs) compared to an isogenic control cell line. Isogenic control cells alongside both heterozygous and homozygous CX3CR1 V249I cell lines were differentiated in parallel to yield enriched populations of hMGLs. Resulting hMGLs were then assessed for uptake of amyloid beta 1‐42 using flow cytometry, cell death in response to cytokine starvation, changes in proliferation, and finally alterations to migratory behavior using a microfluidic chamber. Result: We demonstrate the effective differentiation of hMGLS from both isogenic control and CX3CR1‐V249I backgrounds, which express characteristic microglial markers and are functionally phagocytic. Microglia bearing the homozygous CX3CR1‐V249I allele, but not heterozygous cells, demonstrated decreased uptake of amyloid beta in vitro compared to isogenic controls. Additionally, homozygous V249I microglia demonstrated increased stress‐induced cell death, as well as altered proliferation and decreased migratory capability. Conclusion: These findings suggest that the CX3CR1‐V249I polymorphism may cause a dysfunctional microglia phenotype that may contribute to neuronal dysfunction and death. Ongoing work will expand upon the transcriptome and secretome profile of CX3CR1‐V249I microglia and elucidate how this gene variant contributes to Alzheimer’s Disease‐related neurodegeneration.Item Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models(Elsevier, 2024) Gomes, Cátia; Huang, Kang-Chieh; Harkin, Jade; Baker, Aaron; Hughes, Jason M.; Pan, Yanling; Tutrow, Kaylee; VanderWall, Kirstin B.; Lavekar, Sailee S.; Hernandez, Melody; Cummins, Theodore R.; Canfield, Scott G.; Meyer, Jason S.; Medical and Molecular Genetics, School of MedicineReactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer's disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.Item More comfortable online? Alexithymia and social media use(Office of the Vice Chancellor for Research, 2016-04-08) Zarins, Sasha; Johnson, Monique; Ustymchuk, Nina; Tutrow, Kaylee; Konrath, Sara H.Abstract: Alexithymia includes difficulty identifying and describing emotions, limited imaginative ability, and a tendency to focus attention on external reality versus inner experience (Taylor, Bagby, & Parker, 1991, 1997). Alexithymia is one feature of low emotional intelligence (Bar-on, 1996, 1997; Parker, Taylor, & Bagby, 2001). There has been limited, conflicting research on the topic of emotional intelligence and social media usage. For example, emotionally intelligent people tend to use Facebook more overall (Bektas, Toros, & Miman, 2014), but tend to use MySpace less for communicating with romantic partners (Dong, Urista, & Gundrum, 2008). Thus, we tentatively hypothesize that alexithymia may be associated with more social media usage because it may be more difficult for these individuals to form strong in-person relationships (Kauhanen, Kaplan, Julkunen, Wilson & Salonen, 1993). 938 online adults (72% female, Mean age=28.10, 84.8% Caucasian) completed the Toronto Alexithymia Scale (TAS-20; Bagby, Parker, & Taylor, 1993) and self-report measures of social media use as part of a larger study. The mean score on the TAS-20 was 44.88 (SD=10.55), with 82 (8.7%) participants having alexithymia (score >=61). Overall, total alexithymia was positively associated with total social media use, β=.06, p=.05. In terms of type of social media, total alexithymia was marginally associated with Facebook use and Instagram use, βs=.06, ps=.06, but was not associated with Twitter use, β=.03, p=.43. When examining active (posting) verse passive use (checking) of social media, total alexithymia was positively associated with active social media use (posting), β=.06, p=.04, but was not associated with passive social media use (checking), β=.05, p=.14. Alexithymia is associated with higher levels of certain types of social media. Future research should directly measure social media usage, rather than rely on self-report. But to our knowledge, this is the first study to examine question of how alexithymic people use social media.Item S‐Nitroso‐L‐cysteine and ventilatory drive: A pediatric perspective(Wiley, 2022) Hubbard, Dallin; Tutrow, Kaylee; Gaston, Benjamin; Pediatrics, School of MedicineThough endogenous S‐nitroso‐l‐cysteine (l‐CSNO) signaling at the level of the carotid body increases minute ventilation (v̇E), neither the background data nor the potential clinical relevance are well‐understood by pulmonologists in general, or by pediatric pulmonologists in particular. Here, we first review how regulation of the synthesis, activation, transmembrane transport, target interaction, and degradation of l‐CSNO can affect the ventilatory drive. In particular, we review l‐CSNO formation by hemoglobin R to T conformational change and by nitric oxide (NO) synthases (NOS), and the downstream effects on v̇E through interaction with voltage‐gated K+ (Kv) channel proteins and other targets in the peripheral and central nervous systems. We will review how these effects are independent of—and, in fact may be opposite to—those of NO. Next, we will review evidence that specific elements of this pathway may underlie disorders of respiratory control in childhood. Finally, we will review the potential clinical implications of this pathway in the development of respiratory stimulants, with a particular focus on potential pediatric applications.