ROLE OF ICAM-1-MEDIATED ENDOCYTOSIS IN ENDOTHELIAL FUNCTION AND IMPLICATIONS FOR CARRIER-ASSISTED DRUG DELIVERY

Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein found on the surface of vascular endothelial cells (ECs). Its expression is upregulated at inflammatory sites, allowing for targeted delivery of therapeutics using ICAM-1-binding drug carriers. Engagement of multiple copies of ICAM-1 by these drug carriers induces cell adhesion molecule (CAM)-mediated endocytosis, which results in trafficking of carriers to lysosomes and across ECs. Knowledge about the regulation behind CAM-mediated endocytosis can help improve drug delivery, but questions remain about these regulatory mechanisms. Furthermore, little is known about the natural function of this endocytic pathway. To address these gaps in knowledge, we focused on two natural binding partners of ICAM-1 that potentially elicit CAM-mediated endocytosis: leukocytes (which bind ICAM-1 via β₂ integrins) and fibrin polymers (a main component of blood clots which binds ICAM-1 via the γ3 sequence). First, inspired by properties of these natural binding partners, we varied the size and targeting moiety of model drug carriers to determine how these parameters affect CAM-mediated endocytosis. Increasing ICAM-1-targeted carrier size slowed carrier uptake kinetics, reduced carrier trafficking to lysosomes, and increased carrier transport across ECs. Changing targeting moieties from antibodies to peptides decreased particle binding and uptake, lowered trafficking to lysosomes, and increased transport across ECs. Second, using cell culture models of leukocyte/EC interactions, inhibiting regulatory elements of the CAM-mediated pathway disrupted leukocyte sampling, a process crucial to leukocyte crossing of endothelial layers (transmigration). This inhibition also decreased leukocyte transmigration across ECs, specifically through the transcellular route, which occurs through a single EC without disassembly of cell-cell junctions. Third, fibrin meshes, which mimic blood clot fragments/remnants, bound to ECs at ICAM-1-enriched sites and were internalized by the endothelium. Inhibiting the CAM-mediated pathway disrupted this uptake. Following endocytosis, fibrin meshes trafficked to lysosomes where they were degraded. In mouse models, CAM-mediated endocytosis of fibrin meshes appeared to remove fibrin remnants at the endothelial surface, preventing re-initiation of the coagulation cascade. Overall, these results support a link between CAM-mediated endocytosis and leukocyte transmigration as well as uptake of fibrin materials by ECs. Furthermore, these results will guide the future design of ICAM-1-targeted carrier-assisted therapies.

VIRTUOSIC ELEMENTS IN THE COLLABORATIVE PIANIST’S REPERTOIRE: SELECTED SOLO, VOCAL, AND CHAMBER WORKS OF RACHMANINOFF AND RAVEL

This dissertation project explores some of the technical and musical challenges that face pianists in a collaborative role—specifically, those challenges that may be considered virtuosic in nature. The material was chosen from the works of Rachmaninoff and Ravel because of the technically and musically demanding yet idiomatic piano writing. This virtuosic piano writing also extends into the collaborative repertoire. The pieces were also chosen to demonstrate these virtuosic elements in a wide variety of settings. Solo piano pieces were chosen to provide a point of departure, and the programmed works ranged from vocal to two-piano, to sonatas and a piano trio. The recitals were arranged to demonstrate as much contrast as possible, while being grouped by composer. The first recital was performed on April 24, 2009. This recital featured five songs of Rachmaninoff, as well as three solo piano preludes and his Suite No. 2 for two pianos. The second recital occurred on November 16, 2010. This recital featured the music of both Rachmaninoff and Ravel, as well as a short lecture introducing the solo work “Ondine” from Gaspard de la nuit by Ravel. Following the lecture were the Cinq mélodies populaires grecques and the program closed with the substantial Rachmaninoff Sonata for Cello and Piano. The final program was given on October 10, 2011. This recital featured the music of Ravel, and it included his Sonata for Violin and Piano, the Debussy Nocturnes transcribed for two pianos by Ravel, and the Piano Trio. The inclusion of a transcription of a work by another composer highlights Ravel’s particular style of writing for the piano. All of these recitals were performed at the Gildenhorn Recital Hall in the Clarice Smith Performing Arts Center at the University of Maryland. The recitals are recorded on compact discs, which can be found in the Digital Repository at the University of Maryland (DRUM).

FOLK ELEMENTS IN TWENTIETH-CENTURY HUNGARIAN MUSIC

At the beginning of the twentieth century, composers Béla Bartók and Zoltán Kodály collected thousands of folksongs from the rural regions of Hungary. In an effort to preserve a part of their culture that they feared would be lost, they not only transcribed and catalogued these folksongs, but also incorporated the folk traditions they encountered into their own compositional style. This dissertation deals with violin music written by Bartók, Kodály and their Hungarian contemporaries that have in common the use of rhythms, modes, melodies, figurations and playing techniques sourced in folk traditions. The use of the Hungarian folk idiom in classical music was not exclusive to the twentieth century. From the late eighteenth century until the first decades of the twentieth century, composers utilized aspects of a popular eighteenth-century form of Hungarian folk music called verbunkos. What makes the use of folk music unique in the twentieth century is that, thanks to the work of Bartók and Kodály, composers found inspiration in the more authentic “peasant music.” Unlike the popular, urban verbunkos music, peasant music was the product of the more secluded village-music tradition, largely untouched by the influences of city life. In addition to stimulating a new focus on peasant music, Bartók and Kodály fully assimilated the folk idiom into their compositional toolkits, creating a new style of folk-inspired art music that influenced a generation of Hungarian composers. The new style included characteristic elements of both peasant music and the verbunkos tradition, such as ancient modes and scales, accompanimental and melodic rhythmic patterns, ornamentation, and phrase structures sourced in folk song. To demonstrate the implementation of the folk idiom by twentieth-century Hungarian composers, three recital programs were given at the University of Maryland that included works by Béla Bartók, Sándor Veress, Leo Weiner, Zoltán Kodály, Ernő Dohnányi, Zoltán Székely and György Kurtág. The works can be divided into two main categories: settings or transcriptions of folk material (e.g. Bartók’s Hungarian Folksongs) and compositions using classical forms that include the Hungarian folk idiom (e.g. Bartók’s Contrasts). Recital collaborators include Li-Tan Hsu, Evelyn Elsing, Elizabeth Brown, Shelby Sender and Samantha Angelo.