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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

TRPV4 Implications in Inflammation and Hydrocephalic Neurological Disease

Simpson, Stafanie J. 05 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Hydrocephalus is a debilitating disease characterized by an increase in cerebrospinal fluid (CSF) in the brain, leading to increases in pressure that can ultimately result in death. Current treatments for hydrocephalus include only invasive brain surgery. Therefore, the need for a pharmaceutical therapy is great. In order to develop a suitable treatment, we first must be able to study the disease and the mechanisms by which it develops. By characterizing appropriate in vivo and in vitro models, we are better able to study this disease. In this thesis, the Wpk rat model and the PCP-R cell line are described as such appropriate models. In addition to suitable models, we also require a target for drug treatment. Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation ion channel present in the main CSF-producing organ in the brain, the choroid plexus (CP). Preliminary data suggest this channel plays a role in the development of hydrocephalus. In the following work, some of the mechanisms by which TRPV4 functions in the brain are also described, including through calcium-sensitive potassium channels and inflammation. From this research, we are able to achieve a better understanding of the function of TRPV4 and how it can affect the development and progression of hydrocephalus.
22

Role of the tumor microenvironment on mechanosensitive TRPV4 channels and tumor angiogenesis

Guarino, Brianna D. 04 August 2021 (has links)
No description available.
23

Hochstetler AE Dissertation 7.26.22.pdf

Alexandra Elizabeth Hochstetler (13154817) 26 July 2022 (has links)
<p>  </p> <p>Pediatric hydrocephalus is a complex neurological condition associated with a pathological accumulation of cerebrospinal fluid (CSF), typically within the brain ventricular system. Pediatric hydrocephalus can be primary (due to genetic abnormalities or idiopathic causes), or secondary to injuries such as hemorrhage, trauma, or infection. The current permanent treatment paradigms for pediatric hydrocephalus are exclusively surgical and include the diversion of CSF via shunt or ventriculostomy. These surgical interventions are wrought with failures, burdening both the United States healthcare system and patients with repeat neurosurgical procedures. Thus, the development of nonsurgical interventions to treat hydrocephalus represents a clinically unmet need. To study hydrocephalus, we use a genetic rat model of primary neonatal hydrocephalus, the <em>Tmem67</em>P394L mutant. In several proof-of-concept studies, we identify antagonism of the transient receptor potential vanilloid 4 (TRPV4) channel and associated upstream regulatory kinase, serum-and-glucocorticoid-induced kinase 1 (SGK1) as therapeutics for the treatment of hydrocephalus. Using <em>in vitro</em> models of the choroid plexus epithelium, the tissue which produces CSF, we show compelling proof-of-mechanism for TRPV4 antagonism and SGK1 inhibition at preventing CSF production. Therefore, the studies in this dissertation provide substantive evidence on the role of TRPV4 in the choroid plexus in health and disease. </p>
24

ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS

Thoppil, Roslin Joseph 24 April 2015 (has links)
No description available.
25

Novel Mechanisms Underlying Warm-up and Percussion Myotonia in Myotonia Congenita

Novak, Kevin Richard 06 June 2017 (has links)
No description available.
26

ROLE OF MECHANOSENSITIVE ION CHANNEL TRPV4 IN CARDIAC REMODELING

Adapala, Ravi kumar 28 March 2018 (has links)
No description available.
27

<b>CHARACTERIZING CHANGES IN THE BRAIN DURING HYDROCEPHALIC DEVELOPMENT AND EXPLORING POTENTIAL TREATMENT STRATEGIES</b>

Makenna Reed (18431391) 03 June 2024 (has links)
<p dir="ltr">A neurological disorder, hydrocephalus, has an estimated global pediatric prevalence of 380,000 new cases each year [<a href="#_ENREF_1" target="_blank">1</a>]. It is a family of diseases that can occur at any age when cerebrospinal fluid builds up within the ventricles of the brain. Thus, the only available treatments are surgical, invasive, and prone to complications. There is a global need for successful treatment strategies without brain surgery.</p><p><br></p><p dir="ltr">Choroid plexus epithelial cells (CPEC) are responsible for production of cerebrospinal fluid (CSF). Ependymal cells line the ventricles and play roles in CSF maintenance and waste clearance. Astrocytes perform various functions, one being blood-brain barrier (BBB) maintenance. Collectively these cells contribute to brain fluid/electrolyte regulation and barrier integrity. Increased glial fibrillary acidic protein (GFAP) fluorescence, a marker of activated astrocytes, appeared in hydrocephalic (<i>Tmem67</i><sup>-/-</sup>) animals by immunohistochemistry as early as postnatal day (P)10. The tight junction proteins expressed in choroid plexus (CP); claudin-1 (Cl-1) and zona occludin 1 (ZO-1) fluorescent intensity increased in P15 hydrocephalic animals compared to wildtype (<i>Tmem67</i><sup>+/+</sup>). These cells also contain aquaporins (AQP), aquaporin-1 (AQP1) and aquaporin-4 (AQP4), important in regulating CSF and interstitial fluid (ISF). Increased fluorescent intensity of AQP4 in the subventricular zone and increased AQP1 apical localization and protein amount in the CP was observed in hydrocephalic animals at postnatal day (P)15. Many of these may be targeted for the treatment of hydrocephalus. However, there is no consensus in pathological findings between models of hydrocephalus and these finding may not translate to common pharmacological targets.</p><p><br></p><p dir="ltr">A transient receptor potential cation channel, subfamily vanilloid, member 4 (TRPV4) antagonist (RN1734) ameliorates hydrocephalus in a rat model of congenital hydrocephalus (<i>Tmem67</i> model). It was hypothesized that targeting this mechanosensitive ion channel may slow production of CSF by targeting the CP. However, hydrocephalus pathology can have various effects on the brain. Astrocytes were visualized using fluorescent immunohistochemistry of glial fibrillary acidic protein (GFAP) and RN1734 did not seem to change immunoreactivity to wildtype untreated levels. Increased immunoreactivity of TRPV4 and AQP1 was observed in CP of untreated and RN1734 treated <i>Tmem67</i><sup>-/-</sup> rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and periventricular white matter (WM) of hydrocephalic rats. With RN1734, TRPV4 immunoreactivity, but not AQP4, had similar immunoreactivity to wildtype untreated. Increased GFAP and AQP immunoreactivity may indicate residual inflammation in the <i>Tmem67</i><sup>-/-</sup> rats. More experiments must be done to further elucidate TRPV4’s role in hydrocephalus pathology.</p><p><br></p><p dir="ltr">Serum and glucocorticoid-regulated kinase 1 (SGK1) is a kinase implicated in cell volume regulation and CSF production. SI113, an SGK1 inhibitor, ameliorates hydrocephalus in the <i>Tmem67</i> rodent model. The goal of this study was to determine if SI113 could be used with a new solvent other than dimethyl sulfoxide (DMSO), which can have possible toxic effects. 1-methyl-2-pyrrolidinone (NMP) has high solubility and ability to cross the BBB. These studies showed that NMP as a solvent did not have adverse effects on body weight, however thus far, it has not ameliorated hydrocephalus significantly at the concentration used in this study. There is a possibility that the concentration in NMP that we used was not efficacious enough. CSF and blood plasma samples from animals treated with SI113 24 hours and 30 minutes before euthanasia will be used to investigate the concentration of SI113 that remains in the circulation and the amount that crosses the BBB and blood-cerebrospinal fluid (BCSFB) barriers. We hope that the results will inform dosage for our future studies. Future studies may also examine SI113 mechanism of action in hydrocephalus.</p><p><br></p><p dir="ltr">This thesis addresses hydrocephalus cell and molecular pathology in the <i>Tmem67</i> model and examines potential treatment strategies. Future directions include comparing models of hydrocephalus to find common treatment strategies in the hope to find pharmaceutical strategies to better manage human hydrocephalus.</p>
28

Calcium dynamics and related alterations in pulmonary hypertension associated with heart failure.

Dayeh, Nour 03 1900 (has links)
No description available.
29

Caracterización fucional y molecular del canal TRPV4 en el epitelio respiratorio y su relación con la fisiopatología de la fibrosis quística

Arniges Gómez, Maite 30 June 2006 (has links)
En este trabajo de tesis doctoral se caracteriza funcional y molecularmente el canal TRPV4 en varios modelos de células epiteliales respiratorias mostrando por primera vez la participación de este canal en la función osmoreguladora a nivel celular así como la identificación de nuevas variantes del canal. Se demuestra que la entrada de Ca2+ en respuesta a un hinchamiento hipotónico se produce a través del canal TRPV4 y es necesaria para una eficiente recuperación del volumen o RVD. Por su parte, las células epiteliales respiratorias con fenotipo de fibrosis quística no son capaces de reducir su volumen en un medio hipotónico a causa de una regulación defectuosa del canal, indicando, al mismo tiempo, que la regulación del TRPV4 por el estímulo hipotónico es dependiente de la CFTR.La caracterización de las variantes del canal TRPV4 demuestra que los dominios de ANK son determinantes moleculares claves en el proceso de oligomerización del canal. Al mismo tiempo este trabajo describe nuevos aspectos relacionados con la biogénesis del TRPV4 hasta ahora desconocidos: la oligomerización del canal tiene lugar en el RE, orgánulo donde es N-glicosilado de forma simple antes de ser transportado hacia el Golgi donde sus N-glicanos son madurados. / This thesis characterizes molecularly and funcionally the TRPV4 channel in various models of airway epithelial cells showing, for the first time, the involvement of this channel in an osmoregulatory cellular function as well as the isolation of new splice variants of this channel. It is demonstrated that the TRPV4 channel is the molecular Ca2+ pathway activated by hypotonic estimulus needed to trigger the RVD response. Furthermore, the cystic fibrosis airway epithelial cells showed an impaired RVD due to the misregulation of the TRPV4 channel, indicating that the regulation by the hypotonic stimulus is CFTR-dependent.The characterization of the new variants demonstrated that the ANK domains are key structural determinants in the oligomerization process of the TRPV4. This work also describes new aspects related to the biogenesis of this channel: oligomerization is achieved in the ER, where the TRPV4 is N-glycosilated and then transported to the Golgi where the glycans are matured.
30

Molecular determinants of TRPV4 channel regulation

Garcia-Elias Heras, Anna 30 June 2011 (has links)
TRPV4 is a non-selective cation channel with a wide expression and multiple cellular and systemic functions. Described initially as an osmosensor, it can also be activated by temperature and cell swelling. Due to this variety of activating stimuli it may have a promiscuous gating behavior which is mostly unknown. This Thesis research aims to get in-depth in the understanding of the molecular determinants of TRPV4 regulation. I provide evidences that the inositol trisphosphate receptor and its modulatory function on TRPV4 relies on its binding to the C-terminal tail of TRPV4. I discuss the role of the channels’ N-terminal tail in osmotransduction and show how a mutation that results in a channel with an impaired response to osmotic environments is associated to a pathophysiological condition such as hyponatremia. I also highlight the importance of this N-terminal tail and the binding to the regulatory protein PACSIN3 for the global conformation of the channel. / El TRPV4 és un canal catiònic no selectiu d’expressió generalitzada i funcions diverses. Tot i que inicialment es va descriure com un osmosensor sistèmic, avui sabem que també es pot activar per temperatura o per augments del volum cel•lular. Degut a la diversitat d’estímuls, el canal presenta diferents vies d’activació la major part de les quals són desconegudes. Aquesta Tesi pretén estudiar en detall els mecanismes moleculars que regulen l’activitat del canal. Aportem evidències del lloc d’unió a la cua C-terminal del receptor d’inositol trifosfat així com la seva modulació sobre l’activitat del TRPV4. També discutim el rol de la cua N-terminal en la osmotransducció i presentem una mutació, generadora d’un canal amb una resposta anòmala a estímuls hipotònics, que està associada a una condició fisiopatològica com la hiponatremia. També destaquem la importància de la cua N-terminal i de la unió de la proteïna reguladora PACSIN3 en la conformació global del canal.

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