No description available.

No description available.

<p dir="ltr">Migraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Na_v1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Na_vs). More work is needed to determine which FHFs affect which Na_vs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Na_v1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.</p>

No description available.

The MOS-gated thyristors (MGT) refer to the class of power devices that combine the ease of a MOS gate control with the superior current carrying capability of a thyristor structure for high-power applications. The MOS-controlled thyristor (MCT) is a typical MGT device. A comprehensive investigation of the reverse-biased safe operating area (RBSOA) characteristics of the MCT has been undertaken. The electrical failure mechanisms of the MCT are discussed, and the relationship between the dynamic avalanche limited RBSOA boundary of the MCT and the lower open-base transistor is identified. An analytical model based on the dynamic current gain concept is proposed to characterize the open-base transistor. For the first time, a RBSOA characteristic equation is developed for the MCT and a unified view of the RBSOA characteristics of the MCT is presented. The fundamental characteristics of the MCT are compared to those of the insulated gate bipolar transistor (IGBT) at two levels: unit-cell and multi-cell. The investigation of the unit-cell level focuses on the tradeoff between the on-state voltage drop, the turn-off loss, and the RBSOA characteristic. The investigation of the multi-cell level reveals the fundamental difference between the MCT and the IGBT in handling the non-uniform turn-off caused by the internal propagation gate delay of a large-area device. Lack of current saturation capability is identified as the main reason for the severe degradation of the turn-off capability of a large-area multi-cell MCT. The current saturation and controlled turn-on capabilities can be realized in the MGT devices with dual operation modes. For the first time, a dual operation mode MCT developed with superior current saturation capability is used to demonstrate how the dual operation device can be beneficial in the switching circuit application. The maximum controllable current density (Jmcc) is the most important characteristic of the dual operation mode MGT devices. A first-order analytic model is developed to characterize the Jmcc of the dual operation mode MGT structures compatible with the IGBT fabrication process. A new device structure with improved Jmcc characteristics is proposed and verified by both simulation and experimental results. The dissertation also carries out a comprehensive investigation of the development of power diodes. A new power diode, called the Trench Bipolar Junction Diode (TBJD), which has superior dynamic characteristics over the conventional P-i-N diode, is proposed. The TBJD controls the anode injection efficiency of the diode by the action of a reverse active transistor structure integrated into its anode junction. The reverse active transistor helps tailor an optimized on-state carrier profile to improve the diode switching characteristics. A novel self-aligned process is developed to fabricate the TBJD. Experimental characterization of the fabricated TBJD devices shows that the TBJD achieves superior dynamic characteristics without sacrificing the on-state voltage drop and the leakage current characteristics. / Ph. D.

Understanding how genetic changes ultimately affect morphology and physiology is essential for understanding and predicting how organisms will adapt to environmental changes. Although most traits are complex and involve the interplay of many different genetic loci, some exceptions exist. These include the convergent evolution of tetrodotoxin resistance in snakes, which has a simple genetic basis and can be used as a model system to investigate the genetic basis of adaptive evolution. Tetrodotoxin is a potent neurotoxin used as a chemical defense by various animals, including toxic newts. Snakes have evolved resistance through mutations in voltage-gated sodium channels, the protein targets of tetrodotoxin, sparking an evolutionary arms race between predator and prey. In this dissertation, I describe how genomic rearrangements have led to sex-linkage of four of the voltage-gated sodium channel genes in snakes and compare allele frequencies across populations and sexes to make inferences about how sex linkage has influenced the evolution of resistance in garter snakes. By measuring gene expression in different snake tissues, I show that three of these sex-linked sodium channel genes are dosage compensated in embryos, adult muscle, and adult brain. In contrast, two channels show sexual dimorphism in their expression levels in the heart, which may indicate differences in dosage compensation among tissues. I then use comparative genomics to track the evolutionary history of tetrodotoxin resistance across all nine sodium channel genes in squamate reptiles and show how historical changes have paved the way for full-body resistance in certain snakes. Finally, I use targeted sequence capture to obtain the sodium channel sequences of salamanders and show evidence that tetrodotoxin self-resistance in toxic newts was likely accelerated through gene conversion between resistant and non-resistant sodium channel paralogs. Together, these results illustrate parallelism in evolutionary mechanisms and processes contributing to the appearance of an extreme and complex trait that arose independently in two distinct taxa separated by hundreds of millions of years. / Doctor of Philosophy / Western North America is the site of an ongoing battle between highly toxic species of salamanders (toxic newts) and their garter snake predators. In certain regions, garter snakes have countered newt defenses by evolving resistance to their toxins, and the newts have become more toxic in response. This interaction has been the focus of scientists for decades because it teaches us about the ways in which animals can respond to changes in their environment. In living organisms, DNA is used a blueprint to determine the ultimate traits that are expressed (e.g., whether an organism will have five fingers or four, or whether it will be resistant or sensitive to a toxin). By comparing DNA sequences of different life forms, we are beginning to understand the rules that determine how these blueprints are read and how they can change over time. Because life is built upon the same basic building blocks (DNA, mRNA, and proteins), information about this snake-newt system can be used to understand the way that other systems, such as humans and pathogens, might interact. In my dissertation, I compare DNA sequences from snakes and lizards to identify the history of changes leading to the extreme toxin resistance in the garter snakes. I show that toxin resistance began hundreds of millions of years ago, with all lizards having a low baseline level of resistance, and that resistance built up slowly in the lineages leading to garter snakes. I also show that because of DNA rearrangements, female snakes have fewer copies of some of the genes involved in resistance, and this may have led to differences among the sexes. Lastly, I compare DNA sequences among salamanders, revealing a similar pattern to that in snakes and lizards. Specifically, newts have evolved self-resistance to their own toxin, and this has happened gradually over hundreds of millions of years, with all salamanders having some toxin resistance. I also show that an unusual process occurred within the DNA of toxic newts, resulting in a rapid change from toxin sensitivity to toxin resistance in some genes. Taken together, this work helps advance our understanding of the processes and limitations that determine how organisms can function and change over time.

<p dir="ltr">Seizure involves a sudden, uncontrolled electrical disturbance of the brain due to many different causes apart from epilepsy, for example, high fever, low level of blood sugar, alcohol withdrawal, and many more, including the infections in the brain. In fact, epilepsy is a group of chronic neurological disorders characterized by recurrent unprovoked sudden-onset seizures. It stands as one of the prevalent brain disorders globally, impacting over 70 million individuals. The origins of epilepsy are multifaceted, coming from a mix of genetic and environmental factors including genetic predispositions, brain-related conditions (like tumors or strokes), infectious diseases, and traumatic brain injuries. Seizures can be partly referred to the dysregulation of ion channels, including voltage-gated sodium channels which will impact the action potential (electrical impulses that are responsible for the communication that takes place between neurons in the brain). These voltage-gated sodium channels mediate the depolarization responsible for the generation and conduction of action potentials. They are crucial in the generation and continuous electrical signals of the tissues that respond rapidly, like the neurons, and thus forming part of their function. In epilepsy, therefore, it is relevant to that domain in which abnormal functions of these sodium channels come up. Any change or dysfunction of these channels affect the excitability of the neurons themselves, with the consequence that an increased probability occurs in which abnormal electrical activity can be generated, hence the convulsions. Voltage-gated sodium channels are made up of large transmembrane proteins, having a single alpha subunit and related beta subunits. The beta subunit is an auxiliary protein that modulates channel gating, kinetics, surface expression, and the unique resurgent current, thereby influencing neuronal excitability and signaling. Resurgent currents represent a kind of current that can develop during action potential repolarization. They are characterized by a resurgent sodium current, the current which follows the initial sodium inflow in depolarization. Resurgent sodium currents are characterized by a rebound increase in sodium current during the repolarization phase of the action potential. Unlike the classic transient sodium current that inactivates rapidly upon membrane depolarization, the resurgent current is facilitated by the partial block and unblock of the sodium 17 channel pore by the β subunit or other intracellular molecules during the repolarization phase. This allows sodium ions to flow into the cell when this blockage removed before it goes to closed state. It is believed widely to be of keen importance in neuronal excitability. The role of resurgent currents in epilepsy is likely genetically influenced with some environmental influence. Genetic mutations and dysregulation of the gene code for voltage-gated sodium channels, especially those related to beta subunits, can be linked to some atypical resurgent current. This increases the chance of having a seizure, which could develop into epilepsy. Four beta subunits have been identified up to now. As such, my investigation will focus on the beta 4 subunit and its possible involvement in increased susceptibility to seizures. My study will involve a genetically modified mouse β4 knockout (K.O) of the voltage-gated sodium channel, which will be compared with a wild type (WT) mouse model. To facilitate this comparison, I will prepare cortical brain slices from both the genetically modified and WT mice using a (Leica VT1200s vibratome). These slices will then be analyzed with multi-electrode arrays to detect electrical activity and measure the neurons' electrical responses. Additionally, I use 4- Aminopyridine, a potassium channel blocker, to stimulate electrical activity in the neurons and brain slices. Using the methodology outlined above, I aimed to investigate the ability to induce and measure neuronal activity in the β4 K.O mouse model. This involved comparing the neuronal activity between the β4 K.O and WT mice in terms of frequency and amplitude. The analysis of the recorded data was performed using Spike2 software, in conjunction with the multi-electrode array recordings. Furthermore, I explored whether variations in temperature (body temp vs 40℃) affect neuronal activity differently in β4 K.O compared to WT mice. In conclusion, my observations revealed that neuronal activity could indeed be induced in the β4 K.O mice, with a noted decrease in the frequency of this activity compared to WT mice, but an increase in amplitude. These outcomes were consistent at both normal body temperature and at an elevated temperature of 40°C, as analyzed using Spike2 software. However, when conducting a statistical analysis using a two-way ANOVA to compare between the β4 K.O and WT mice, and between body temperature and 40°C conditions, no significant differences were observed. Despite this, it is a general observation and conclusion that β4 K.O mice exhibit altered neuronal activity 18 compared to WT mice. To gain a deeper understanding of the role of the β4 subunit on the alpha subunit of the voltage-gated sodium channel, adopting alternative methods such as patch clamp techniques or in vivo studies with intracranial electrodes may be beneficial. This suggestion comes considering various challenges and limitations encountered during my study, such as maintaining the viability of the slices for extended periods and minimizing noise in multi-electrode array (MEA) recordings. Mutations of β-subunit-encoding genes have been associated with such a wide array of debilitating diseases that include epilepsy, cancer, neuropathic pain, and febrile seizures, to some of the most prevalent conditions in neurodegeneration. Further study will be needed to better understand the biology of these important proteins and their potential for use as new targets for several disease states. Even so, the role of β4 remains somewhat controversial.</p>

No / Prolonged hyperglycaemia impairs vascular reactivity and inhibits voltage-activated K+ (Kv) channels. We examined acute effects of altering glucose concentration on the activity and inhibition by endothelin-1 (ET-1) of Kv currents of freshly isolated rat arterial myocytes. Peak Kv currents recorded in glucose-free solution were reversibly reduced within 200 s by increasing extracellular glucose to 4 mm. This inhibitory effect of glucose was abolished by protein kinase C inhibitor peptide (PKC-IP), and Kv currents were further reduced in 10 mm glucose. In current-clamped cells, membrane potentials were more negative in 4 than in 10 mm glucose. In 4 mmd-glucose, 10 nm ET-1 decreased peak Kv current amplitude at +60 mV from 23.5 ± 3.3 to 12.1 ± 3.1 pA pF−1 (n = 6, P < 0.001) and increased the rate of inactivation, decreasing the time constant around fourfold. Inhibition by ET-1 was prevented by PKC-IP. When d-glucose was increased to 10 mm, ET-1 no longer inhibited Kv current (n = 6). Glucose metabolism was required for prevention of ET-1 inhibition of Kv currents, since fructose mimicked the effects of d-glucose, while l-glucose, sucrose or mannitol were without effect. Endothelin receptors were still functional in 10 mmd-glucose, since pinacidil-activated ATP-dependent K+ (KATP) currents were reduced by 10 nm ET-1. This inhibition was nearly abolished by PKC-IP, indicating that endothelin receptors could still activate PKC in 10 mmd-glucose. These results indicate that changes in extracellular glucose concentration within the physiological range can reduce Kv current amplitude and can have major effects on Kv channel modulation by vasoconstrictors.

Tesis por compendio / [ES] La presente tesis doctoral titulada "Nanomateriales con puertas moleculares como plataforma de liberación controlada de fármacos para el tratamiento de desórdenes inflamatorios" se centra la preparación y evaluación de nanomateriales híbridos orgánico-inorgánicos, basados en nanopartículas mesoporosas de sílice, para la liberación controlada de fármacos en aplicaciones biomédicas, en concreto en el campo de la inflamación. En primer lugar se describe un nanomaterial para la liberación controlada del inhibidor de caspasa-1, VX-765, aprovechando la acumulación preferencial de las nanopartículas en las zonas inflamadas. En concreto, se han preparado nanopartículas mesoporosas de sílice, cargadas con el fármaco VX-765 y funcionalizadas covalentemente con ¿-poli-L-lisina que actúa como puerta molecular. La actividad anti-inflamatoria del material se ha comprobado tanto in vitro, en el modelo celular de monocitos THP-1, como in vivo en ratones en un modelo de inflamación de bolsa de aire. Los resultados muestran la acumulación preferente de las nanopartículas en las zonas inflamadas así como un aumento del efecto terapéutico del fármaco que se atribuye a las ventajas que ofrece la encapsulación. Se concluye que las nanopartículas mesoporosos de sílice con puertas moleculares podrían ser una herramienta importante para el desarrollo de nuevas estrategias terapéuticas en el campo de la inflamación. Basándonos en los resultados obtenidos, en el capítulo cuatro se describe un sistema de liberación controlada para el tratamiento de la inflamación pulmonar aguda como terapia alternativa que permita la administración directa de fármacos a los pulmones. Se ha preparado un nanosistema basado en nanopartículas mesoporosas de sílice cargadas con el glucocorticoide dexametasona y funcionalizadas covalentemente con una puerta molecular peptídica que reconoce el receptor del factor de necrosis tumoral 1 (TNFR1), que a su vez actúa como agente diana para la acumulación preferente en macrófagos pro-inflamatorios. La actividad terapéutica del sistema se ha corroborado en ensayos in vitro en macrófagos pro-inflamatorios, e in vivo en un modelo de ratón de inflamación pulmonar aguda. Se ha comprobado la acumulación preferente de las nanopartículas en los pulmones inflamados, así como la mejora del efecto terapéutico de la dexametasona en la reducción del daño pulmonar, minimizando los efectos adversos asociados a la administración del fármaco libre. Con todo ello se concluye que las nanopartículas mesoporosas de sílice pueden ser utilizadas para el tratamiento de la inflamación pulmonar aguda pudiendo ser una herramienta útil para superar las limitaciones de los tratamientos actuales. Finalmente, se describe otro sistema de liberación controlada de fármacos para inflamación pulmonar aguda. En este caso, se aborda el uso de un nuevo inhibidor del inflamasoma, QM-378, como terapia farmacológica alternativa. Con el objetivo de potenciar la administración directa en los pulmones inflamados, el QM-378 se encapsula en nanopartículas mesoporosas de sílice funcionalizadas con la puerta molecular peptídica que reconoce TNFR1. La acumulación preferente de las nanopartículas en los pulmones inflamados queda demostrada a través de los ensayos de biodistribución, así como la mejora del efecto terapéutico del QM-378 en la reducción del daño pulmonar, debido a las ventajas de la encapsulación en un nanosistema dirigido. Con todo ello se concluye que el QM-378 es un buen candidato para el tratamiento de la inflamación pulmonar aguda, y que su encapsulación en las nanopartículas ofrece una administración pulmonar directa y controlada, consiguiéndose así una mejora en el perfil terapéutico del fármaco. La conclusión principal de la presente tesis doctoral es que el desarrollo de nanomateriales mesoporosos de sílice para la liberación controlada de fármacos se presenta como un / [CA] La present tesi doctoral titulada "Nanomaterials amb portes moleculars com a plataforma d'alliberament controlat de fàrmacs per al tractament de desordres inflamatoris" se centra en la preparació i avaluació de nanomaterials híbrids orgànic-inorgànics, basats en nanopartícules mesoporoses de sílice, per a l'alliberament controlat de fàrmacs en aplicacions biomèdiques, en concret en el camp de la inflamació. En primer lloc, es presenta un nanomaterial per a l'alliberament controlat de l'inhibidor de caspasa-1, VX-765, aprofitant que les nanopartícules s'acumulen preferencialment en les zones inflamades. S'han preparat nanopartícules mesoporoses de sílice, carregades amb VX-765 i funcionalitzades covalentment amb ¿-poli-L-lisina com a porta molecular. L'activitat anti-inflamatòria del material s'ha comprovat tant in vitro, en el model cel·lular de THP-1, com in vivo en ratolins en un model d'inflamació de bossa d'aire. Els resultats mostren la acumulació preferent de les nanopartícules en les zones inflamades així com un augment de l'efecte terapèutic del fàrmac, atribuÏt als avantatges que ofereix l'encapsulació. Es conclou que les nanopartícules mesoporoses de sílice amb porta molecular podrien ser una eina important per al desenvolupament de noves estratègies terapèutiques en el camp de la inflamació. Basant-nos en els resultats obtinguts, en el capítol quatre es presenta un sistema d'alliberament controlat per al tractament de la inflamació pulmonar aguda com a teràpia alternativa que permet l'administració directa de fàrmacs als pulmons. S'ha preparat un nanosistema basat en nanopartícules mesoporoses de sílice carregades amb el glucocorticoide dexametasona i funcionalitzades amb la unió covalent de una porta molecular peptídica que reconeix el receptor del factor de necrosi tumoral 1 (TNFR1), que al seu torn actua com a agent diana per a la acumulació preferent en macròfags pro-inflamatoris. L'activitat terapèutica del sistema dissenyat s'ha corroborat en assajos in vitro en macròfags pro-inflamatoris, i in vivo en un model de ratolí d'inflamació pulmonar aguda. S'ha comprovat la acumulació preferent de les nanopartícules en els pulmons inflamats a través d'assajos de biodistribució, així com la millora de l'efecte terapèutic de la dexametasona en la reducció de la lesió pulmonar minimitzant els efectes adversos associats a l'administració del fàrmac lliure. Amb tot això es conclou que les nanopartícules mesoporoses de sílice poden ser utilitzades per al tractament de la inflamació pulmonar aguda ja que poden ajudar a superar les limitacions dels tractaments actuals. Finalment es mostra també un sistema d'alliberament controlat de fàrmacs per a inflamació pulmonar aguda. En aquest cas, es descriu l'ús d'un nou inhibidor de l'inflamasoma, QM-378, com a teràpia farmacològica alternativa al tractament de la inflamació descontrolada en la inflamació pulmonar aguda. Amb l'objectiu de potenciar l'administració directa en els pulmons inflamats, el QM-378 s'encapsula en les nanopartícules mesoporoses de sílice funcionalitzades amb la porta molecular péptidica que reconeix TNFR1. La acumulació preferent de les nanopartícules en els pulmons inflamats queda demostrada a través dels assajos de biodistribució, així com la millora de l'efecte terapèutic del QM-378 en la reducció de la inflamació pulmonar, atribuït als avantatges de l'encapsulació en un nanosistema dirigit. Amb tot això es conclou que el QM-378 és un bon candidat per al tractament de la inflamació pulmonar aguda, i que la seua encapsulació en les nanopartícules ofereix una administració pulmonar directa i controlada aconseguint-se així una millora en el perfil terapèutic del fàrmac. La conclusió principal és que el desenvolupament de nanomaterials mesoporosos de sílice per a l'alliberament controlat de fàrmacs es presenta com una estratègia amb molt potencial en el camp de les / [EN] This PhD thesis entitled "Gated nanomaterials as delivery platform to manage inflammatory disorders" is focused on the design, synthesis and evaluation of hybrid organic-inorganic nanomaterials using mesoporous silica nanoparticles, for controlled drug release in biomedical applications, specifically in the field of inflammation. In a fist step, we present a new nanodevice for the controlled delivery of VX-765, a caspase 1 inhibitor, which takes advantage of the intrinsic passive targeting effect of the nanoparticles to inflamed tissues. In particular, mesoporous silica nanoparticles loaded with the drug VX-765 and functionalized with ¿-poly-L-lysine (acting as gatekeeper) have been prepared. The anti-inflammatory activity of the prepared nanodevice has been evaluated both in vitro, in the cellular model of monocytes THP-1, and in vivo using air pouch mouse as model of inflammation. The results showed the preferential accumulation of the nanoparticles in the inflamed tissue, as well as an increase in the therapeutic effect of the entrapped drug. As conclusion, gated mesoporous silica nanoparticles constitute an important tool for the development of new therapeutic strategies in the inflammatory field. Based on the previous results presented, a drug delivery system for the treatment of acute lung injury is described in chapter four as alternative therapy that allow the direct delivery of drugs into the lungs. Mesoporous silica nanoparticles has been prepared, loaded with the glucocorticoid dexamethasone and capped with a peptide gatekeeper that recognizes the receptor of tumour necrosis factor 1 (TNFR1), which also targets the pro-inflammatory macrophages. The therapeutic activity of the designed nanoparticles has been studied in vitro in pro-inflammatory macrophages, and in vivo in an acute lung injury mouse model. The preferential accumulation of the nanoparticles in the inflamed lungs has been corroborated through biodistribution assays, as well as the ability to enhance the dexamethasone therapeutic effect by the reduction of lung injury and minimizing the undesired side effects associated of the free drug administration. As conclusion, gated mesoporous silica nanoparticles can be used for the treatment of acute lung injury and represent a potential tool to overcome the limitations of current treatments. Finally, a drug delivery system for acute lung injury is also presented. In this case, we use the novel inflammasome inhibitor QM-378 as pharmacological alternative therapy to the treatment of uncontrolled inflammation in acute lung injury. With the aim of enhancing the direct drug delivery in lungs, QM-378 is encapsulated in mesoporous silica nanoparticles capped with a peptidic gate that recognizes TNFR1. The preferential accumulation of nanoparticles to inflamed lungs has been also corroborated through biodistribution assays. An enhancement of the therapeutic effect of QM-378 by reducing lung inflammation is demonstrated, due to the advantages of drug encapsulation in a targeted-lung nanosystem. As conclusion, the QM-378 is a suitable candidate for acute lung injury treatment, and its encapsulation in mesoporous silica nanoparticles offers a direct lung drug delivery thus improving the therapeutic profile of the drug. The principal conclusion from this PhD thesis is that the preparation of mesoporous silica nanoaprticles for drug delivery is presented as potential strategy in the field of inflammatory disorders. / García Fernández, A. (2019). Gated nanomaterials as delivery platform for the treatment of inflammatory disorders [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/132694 / Compendio

Voltage-gated sodium channels are composed of pore-forming α-subunits, and modulatory and multifunctional associated β subunits. While much of the field of cardiac electrophysiology and pathology has focused on treating and preventing cardiac arrhythmias by targeting the α subunit, there is also evidence that targeting the β subunits, particularly SCN1B, the gene that encodes β1 and an alternatively spliced variant β1B, has therapeutic potential. The first attempt at targeting the β1 subunit was with the generation of and treatment with an SCN1B Ig domain mimetic peptide βadp1. Here we describe further investigation into the function and mode-of-action of both βadp1 and novel peptides derived from the original βadp1 sequence. We find that in a heterologous expression system βadp1 initially disrupts β1-mediated trans-homophilic adhesion, but after approximately 30 hours eventually increases adhesion. Novel mimetic dimers increase β1 adhesion up to 48 hours post-treatment. Furthermore, it appears that βadp1 may increase β1 adhesion by upregulating the intramembrane proteolysis of β1, a process which has important downstream implications and effects on translation. Despite these exciting findings, we were unable to translate them into a primary culture of cardiac cells with endogenous expression of β1 because we found that both neonatal rat cardiomyocytes and isolated adult mouse cardiomyocytes do not express β1 at detectable levels, whereas they do appear to express β1B. In summary, we show exciting findings on the function and mode-of-action of SCN1B mimetic peptides and their therapeutic potential in targeting the β1 subunit, but further work is needed to determine the translatability of our findings to in vivo models and eventually to humans. / Doctor of Philosophy / Voltage-gated sodium channels have two main parts: the pore-forming α-subunits and the modulatory β subunits. Most research in heart function and issues has focused on fixing problems with the α subunit. However, there's evidence that working on the β subunits, specifically the SCN1B gene that makes β1 and another version called β1B, could be helpful. Previously, researchers used a peptide that is designed exactly like a part of β1, called βadp1, to target the β1 subunit. In our study, we explore more about how βadp1 works and test new peptides based on βadp1. We found that βadp1 initially disrupts trans-homophilic adhesion, where 2 β1 subunits interact with each other across the space between 2 cells, but after about 30 hours, it actually increases adhesion. New mimetic dimers also boost adhesion up to 48 hours later. It seems like βadp1 might enhance adhesion by triggering a process called intramembrane proteolysis of β1, which has important effects on translation. Despite these exciting findings, we couldn't confirm the presence of this protein in heart cells because we discovered that certain heart cells don't have enough β1, although they do have β1B. In conclusion, our study shows promising results about how SCN1B mimetic peptides work and their potential for treating arrhythmia. However, more research is needed to see if these findings apply to real-life situations and eventually to help people with cardiac conduction abnormalities.