In order to maintain the system reliability and minimize the impact of faults in a distribution system, a timely restoration is needed which requires accurate fault localization. Locating High Impedance Faults (HIFs) is specifically challenging because of their variable and nonlinear nature. Most existing approaches focuses on identifying the accurate fault distance occurring in the main trunk of a system, often leaving lateral branches as blind spots. To find the accurate distance to the fault in a lateral branches, a single ended fault location algorithm is proposed that uses synchronized voltage and current measurements from PMUs positioned along the trunk. Initially, a specific model that incorporates the particular characteristics of the fault is developed in the spectral domain. Subsequently, a fault location algorithm is developed that utilizes the change in a voltage of a healthy phase for calculating the accurate distance to the fault. Extensive simulations performed across different systems at different conditions proves the efficacy of the algorithm. Notably, a critical prerequisite for the algorithm's success is the presence of at least one healthy phase running parallel to the faulty phase. / Master of Science / High Impedance Faults (HIFs) in power systems often involve dangerous arcing, posing significant risks to life and property. Accurate fault location is essential to ensure timely restoration of power and mitigate hazards. While existing literature typically focuses on the location of faults in the main trunk lines, distribution systems with numerous lateral branches require precise fault distance determination in these branches for faster restoration. This study introduces a novel approach leveraging Phasor Measurement Units (PMUs) in main feeders to pinpoint fault distances in lateral branches. By analyzing voltage variations in healthy phases, the algorithm accurately determines the distance to the fault in the affected phase. Extensive testing across various systems demonstrates the algorithm's high accuracy. The presence of a healthy phase parallel to the faulty phase is essential for the working of this algorithm. This approach offers a promising solution for enhancing the accuracy of fault location in distribution systems, thereby improving outage response times.

La voie de l’hypoxie cellulaire, contrôlée par le facteur induit par l’hypoxie, est un processus permettant aux cellules de s’adapter à un changement des niveaux d’oxygène ambiant de leurs milieux en stimulant des gènes de la glycolyse qui permettent d’adapter la production d’ATP essentielle à la survie cellulaire. Celle-ci permet de conserver une respiration cellulaire efficace ainsi que de réduire la quantité de substances néfastes pour la cellule. Cette voie a été étudiée dans le contexte du syndrome de Leigh type Canadien-Français, maladie rare causée par une mutation du gène leucine-rich pentatricopeptide repeat containing (LRPPRC) qui entraîne une diminution de l’activité de l’enzyme cytochrome c oxydase et cause un déficit dans la production d’énergie. Bien que l’implication de cette voie ait été rejetée dans le contexte de cette maladie au niveau génétique, cette étude a permis d’identifier l’enzyme NADH déshydrogénase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2), qui est responsable de l’inhibition du complexe I en situation d’hypoxie. Cette protéine pourrait être un mécanisme de compensation dans le syndrome de Leigh type Canadien-Français. La suite logique de cette étude devrait avoir comme objectif d’évaluer les différences entre le profil protéique (niveau des protéines de la voie de l’hypoxie) selon le degré d’atteinte (sévérité clinique) des patients atteints du syndrome de Leigh type Canadien-Français.

Le facteur de transcription HIF-1 ±hypoxia-inducible factor-1¿ est responsable de la réponse cellulaire à l'hypoxie. Cependant, il y a également des activateurs non-hypoxiques de HIF-1 incluant des hormones et des facteurs de croissance. L'angiotensine II (Ang II), l'hormone effectrice dans le système rénine-angiotensine, est un activateur non-hypoxique de HIF-1 puissant dans les cellules musculaires lisses vasculaires (CMLVs). Cette activation par Ang II implique des mécanismes de transcription, de traduction et de stabilisation protéiques. De plus, les espèces réactives d'oxygène (ERO) sont impliquées dans l'augmentation de la stabilisation de HIF-1 pendant un traitement à l'Ang II. Ce travail a pour but d'élucider le rôle des générateurs d'ERO dans l'induction de HIF-1 par l'Ang II dans les CMLVs. Ni un ARN interférence contre la sous-unité p22 de la NADPH oxydase ni le traitement avec un inhibiteur spécifique de la NADPH oxydase n'ont permi de diminuer l'accumulation de HIF-1 par l'Ang II. Néanmoins, l'inhibition pharmacologique du complexe III de la mitochondrie, l'épuisement cellulaire de la protéine mitochondriale Rieske Fe-S et le traitement des cellules avec un antioxydant mitochondrial diminuent de façon importante l'accumulation de HEF-1. En outre, l'inhibition des ERO mitochondriales (mtERO) supprime la stabilisation de HIF-1 et la transcription de gènes dépendante de HIF-1 par l'Ang II. De nombreuses études impliquent les ERO générées par la NADPH oxydase dans les voies de signalisation suivant la stimulation des CMLVs par l'Ang IL Toutefois, nos travaux identifient les mtERO et non les ERO dérivées de la NADPH oxydase comme étant des intermédiaires essentiels dans l'accumulation et la stabilisation de HIF-1.

Le facteur induit par l’hypoxie 1 (Hypoxia-inducible factor-1, HIF-1) est un facteur de transcription clé dans la réponse cellulaire au stress hypoxique. Entre autres, HIF-1 permet le maintien de l’homéostasie de l’oxygène en situations hypoxiques par l’activation de plusieurs gènes impliqués dans divers processus cellulaires et physiologiques. Outre son rôle physiologique important, HIF-1 est également impliqué dans la pathogenèse de nombreuses maladies. Ce facteur est un complexe constitué de deux sous unités, α et β. Contrairement à HIF-1β qui est constitutive, HIF-1α est hautement sensible à l’oxygène. En condition normale d’oxygène, la sous-unité HIF-1α est dégradée par le protéasome à la suite de son hydroxylation. Cependant, en hypoxie, l’hydroxylation et la dégradation de HIF-1α sont inhibées, ce qui se traduit par une stabilisation de HIF-1α et une activation du complexe transcriptionnel HIF-1. Divers autres mécanismes permettent également un contrôle précis de l’activité de HIF-1 afin d’assurer une réponse adaptative adéquate à l’hypoxie. Les travaux présentés dans cette thèse visent à élucider des nouveaux mécanismes de régulation de la sous-unité HIF-1α. Dans un premier temps, nous démontrons la contribution de la prolyl isomérase Pin1 dans la régulation post-traductionnelle de HIF- 1α. Nos travaux indiquent que l’isomérisation de HIF-1α par Pin1 joue un rôle clé dans la régulation de l’activité du complexe HIF-1 et permet une régulation différentielle de ses gènes cibles. Dans un deuxième temps, nous montrons un rôle crucial de Pin1 dans la régulation transcriptionnelle de HIF-1α. Plus précisément, nous montrons l’implication de Pin1 dans la régulation de l’activité de régulateurs positifs de l’expression de HIF-1α, les facteurs de transcription Sp1 et Sp3, ainsi que l’impact de cette régulation sur l’activation du promoteur du gène HIF-1A. Finalement, nous présentons le composé PD184161, un inhibiteur de la voie p42/p44 MAPK, comme un puissant inhibiteur sélectif de la sous-unité HIF-1α. En ce sens, PD184161 permet de bloquer spécifiquement l’accumulation de la protéine HIF-1α induite par des activateurs non-hypoxiques via un mécanisme dépendant de la stabilité mais indépendant de la voie p42/p44 MAPK. Bref, la détermination des nouveaux mécanismes moléculaires modulant l’activité du facteur HIF-1 dans diverses conditions permet une meilleure compréhension des modes de régulation des voies de signalisation hypoxique induites par HIF-1 dans des conditions physiologiques ou pathologiques et aura, par conséquent, un impact majeur sur le développement des stratégies thérapeutiques efficaces. / Hypoxia-inducible factor (HIF-1) is a key transcription factor for the cellular response to hypoxic stress. HIF-1 allows the maintenance of oxygen homeostasis under hypoxic situations by activating several genes involved in various cellular and physiological processes. In addition to its important physiological role, HIF-1 is also implicated in the pathogenesis of many diseases. This factor is a complex composed of two subunits, α and β. In contrast to HIF-1β which is constitutive, HIF-1α is highly sensitive to oxygen. Under normal oxygen conditions, the HIF-1α is degraded by the proteasome following its hydroxylation. In contrast, and under hypoxia, hydroxylation and degradation of HIF-1α are impeded, resulting in HIF-1α stabilization and activation of the HIF-1 transcriptional complex. To ensure an adequate adaptive response, different molecular mechanisms play important regulatory roles for the precise control of HIF-1 activity. The work presented in this thesis aims to elucidate new mechanisms implicated in the regulation of the HIF-1α subunit. We begin by demonstrating the contribution of the prolyl isomerase Pin1 in the post-translational regulation of HIF-1α. Our results indicate that HIF-1α isomerization by Pin1 plays a central role in the regulation of HIF-1 complex activity and leads to a differential regulation of its target genes. Then, we show the pivotal role played by Pin1 in the transcriptional regulation of HIF-1α. More precisely, we provide a comprehensive investigation of the involvement of Pin1 in regulating the activity of positive regulators of HIF-1α expression, the transcription factors Sp1 and Sp3, and the impact of this regulation on HIF-1A gene promoter activation. Finally, we present the compound PD184161, a p42/p44 MAPK pathway inhibitor, as a potent selective inhibitor of the HIF-1α subunit. Indeed, PD184161 specifically blocks HIF-1α protein accumulation induced by nonhypoxic activators through a mechanism dependent on HIF-1α stability but independent of p42/p44 MAPK pathway activation. In summary, the determination of novel molecular mechanisms modulating the HIF-1 transcription factor activity under various conditions leads to a better understanding of hypoxic signaling pathways induced by HIF-1 under both physiological, or pathological, conditions. Therefore, these studies may have an important impact on the development of effective therapeutic strategies in this field.

Molecular biology has entered an era of systematic and automated experimentation. High-throughput techniques have moved biology from small-scale experiments focused on specific genes and proteins to genome and proteome-wide screens. One result of this endeavor is the compilation of complex networks of interacting proteins. Molecular biologists hope to understand life's complex molecular machines by studying these networks. This thesis addresses tree open problems centered upon their analysis and quality assessment. First, we introduce power graph analysis as a novel approach to the representation and visualization of biological networks. Power graphs are a graph theoretic approach to lossless and compact representation of complex networks. It groups edges into cliques and bicliques, and nodes into a neighborhood hierarchy. We demonstrate power graph analysis on five examples, and show its advantages over traditional network representations. Moreover, we evaluate the algorithm performance on a benchmark, test the robustness of the algorithm to noise, and measure its empirical time complexity at O (e1.71)- sub-quadratic in the number of edges e. Second, we tackle the difficult and controversial problem of data quality in protein interaction networks. We propose a novel measure for accuracy and completeness of genome-wide protein interaction networks based on network compressibility. We validate this new measure by i) verifying the detrimental effect of false positives and false negatives, ii) showing that gold standard networks are highly compressible, iii) showing that authors' choice of confidence thresholds is consistent with high network compressibility, iv) presenting evidence that compressibility is correlated with co-expression, co-localization and shared function, v) showing that complete and accurate networks of complex systems in other domains exhibit similar levels of compressibility than current high quality interactomes. Third, we apply power graph analysis to networks derived from text-mining as well to gene expression microarray data. In particular, we present i) the network-based analysis of genome-wide expression profiles of the neuroectodermal conversion of mesenchymal stem cells. ii) the analysis of regulatory modules in a rare mitochondrial cytopathy: emph{Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes} (MELAS), and iii) we investigate the biochemical causes behind the enhanced biocompatibility of tantalum compared with titanium.

Un estudio hermenéutico sobre la obra de Joan Miró. La obra mironiana contiene "una intencionalidad secreta y está inscrita no ámbito de la cabalística". Por este motivo, posibilita establecer algunas relaciones con la obra esotérica de "El Bosco" y con la mística obra de Kandisky. La parte central del estudio está dedicada a desvelar los significados: 1o) de los 20 signos de su Cortège des obsessions, siempre recurrentes en su obra y cuyo simbolismo cabalístico definiría el espíritu semita-catalán de su autor (I Parte); 2o) de "La Masia", como "metáfora mayor del habitar (existir, en sentido heideggeriano), poético- mí(s)tico del artista"(II Parte); 3o) de los "Autorretratos, cuyo discurso poético "traduce el acaecer concreto y real del devenir de su ser humano y artístico (III Parte). Así, el estudio tienta desvelar las fuentes místico-semitas,cuyas verdades dirigieron la vida y el quehacer creativo de Miró, siempre movido por una responsabilidad ética. Las conclusiones de esta lectura interpretativa son expuestas en la IV Parte del estudio. Esta lectura conjuga conocimientos sobre la teoría del arte y el poder creativo del espíritu humano y su capacidad simbólica. El estudio procesa un continuo diálogo entre el arte y la filosofía/psicología, de modo que el saber filosófico fenomenológico o existencial ayuda a entender la obra de Miró,y ésta, a su vez., ilumina la verdad del conocimiento filosófico-existencial. / An hermenéutic study about Miro's work. The mironian artistic work contains" a secret intentionality and is inscribed in a cabalistic sphere". Therefore, it allows some relations with the esoteric work of El Bosco and with the mistic work of Kandinsky. This study dedicates special attention to the meaning of those pictorial works: 1a) The Cortège des obsessions (collection of twenty signs)always recurrent in his work, whose symbolism will reveal the mironian semitic-catalanian Weltanschauung (Part I) ; 2a) "La Masia", "as the main metaphor of his poétic and mythic/mystic dwuelt"(exist, in heideggerian sense).(Part II) ; 3a) The Self-autorretrats, whose poetic oration translates "the real and concrete happening of his human and artistic becoming, (Part III) Thus, the study tries to discover the mystic- semitic sources from which truths Miro dealt his life and his artistic work, always moved by ethical responsability. The conclusions of this interpretative reading are exposed in Part IV. This reading conjugates knowledges about art's theory and creative power of the human mind and its simbolic capacity. This study processes a continuous dialogue between art and philosophy/psychogy in a way that phenomenological or existential philosophy helps to undesrtand Miró's work, which, by it's turn,enlightens the truth of philosophic-existential knowledge.

No description available.

Mammalian promoters often contain DNA-elements that can be bound by a number of closely related transcription factors (TFs) that cannot bind to the same DNA-element simultaneously. It is possible that each TF responds to distinct cues, allowing the gene to be activated in response to multiple stimuli. An alternative possibility is that each TF binds sequentially, each contributing to the pre-initiation events leading up to transcription. Here, we explore the exchange of basic-Helix-Loop-Helix-Leucine-Zipper (bHLH-LZ) factors, USF1, USF2 and MITF at the TYROSINASE promoter following induction by UVB-irradiation and methotrexate-administration. We demonstrate, for the first time in human melanoma, differential induction kinetics of TYROSINASE gene in response to an initial or re-induction, a phenomenon akin to "transcription memory" previously described in yeast. We also show that USF2, specifically detected by two different antibodies targeting the N-terminal region, is largely cytoplasmic, at least in the cell lines we have investigated. We also showed that nucleo-cytoplasmic shuttling of these USF2 species is partly regulated by glucose. Using deletion mutants, we demonstrated the requirement of the amino-acids surrounding the USF-specific region and the basic domain in nuclear localisation of USF2, and that amino-acids 1−193 appear to enhance dimerization of USF2 in addition to the classical HLH-LZ dimerization domain. We will further investigate the role(s) played by MYC, MITF, HIF and USF exchange at common targets (which we identified through our ChIP-seq analysis) in gene activation and the effect on the (re)activation potential of these genes when DNA-binding by one or more of these factors are abolished, as well as when the promoter is monopolised by one of these factors through overexpression using cell lines expressing one of the bHLH-TFs under a tet-inducible promoter. In the long run, we aim to understand the potential differences in the role(s) of each bHLH-factors co-occupying E-box elements.

L'angiogènesis, el desenvolupament de nous vasos sanguinis a partir de vasculatura preexistent, és un procés complex que involucra múltiples productes gènics expressats per diferents tipus cel.lulars, i tots ells contribueixen a una seqüència integrada de fenòmens. L'angiogènesis és necessària per tal de permetre el creixement tumoral més enllà d'una certa mida. La hipòxia, un fenomen inherent en els tumors, és un dels factors principals que desencadena el procés angiogènic. En concordança amb el fet que la hipòxia juga un paper clau en tot el procés, un nombre elevat de gens involucrats en diferents processos de l'angiogènesis, incloent el factor de creixement de l'endoteli vascular (VEGF), responen de manera independent a la hipòxia. El principal mecanisme de resposta dels tumors a nivells reduïts d'oxigen és a través de l'activació del factor induïble per hipòxia-1 (HIF-1). HIF-1 és un heterodímer format per dues subunitats; el factor sensible a la hipòxia HIF-1, i el factor no regulable HIF-1. En presència d'oxigen, HIF-1 és hidroxilat i això permet la seva interacció amb la proteïna supressora de tumors Von Hippel Lindau (VHL) que produirà la seva subseqüent i ràpida degradació a través del proteasoma. En absència d'oxigen, HIF-1 és estabilitzat i és transportat cap al nucli cel.lular on heterodimeritza amb HIF-1, unint-se llavors als llocs de resposta a la hipòxia (HRE) i activant la transcripció de nombrosos gens que juguen un paper fonamental en la supervivència tumoral, l'adaptació metabòlica i l'angiogènesis.Per tant, el desenvolupament d'agents capaços d'inhibir l'angiogènesis ha esdevingut una important modalitat terapèutica. Fruit dels bons resultats en estudis preclínics, diversos agents antiangiogènics sols o en combinació amb teràpies convencionals estan en fase de desenvolupament clínic. Entre aquests agents trobem el 2-Metoxiestradiol (2ME2), un metabolit natural de l'estradiol, actualment en avaluació clínica com a inhibidor de l'angiogènesis tumoral. Diversos estudis han demostrat que el 2ME2 és una molècula petita, mot ben tolerada i que posseeix activitats antitumorals i antiangiogèniques en diferents models in vivo. In vitro, el 2ME2 és capaç d'unir-se a la tubulina al lloc d'unió a la colchicina i despolimeritzar els microtúbuls en interfase, produint arrest en mitosi i la posterior mort cel.lular en línies cel.lulars tumorals. A més a més, s'ha mostrat l'abilitat de diferents agents amb capacitat per inhibir la funció dels microtúbuls, sobretot d'aquells que s'uneixen al lloc d'unió a la colchicina, per fer desaparèixer ràpidament la vasculatura tumoral. Tot i això, encara que s'han proposat diferents mecanismes d'acció per al 2ME2, el seu mecanisme d'acció encara no està ben definit. La nostra hipòtesi és que el 2ME2 inhibeix l'angiogènesis tumoral mitjançant la inhibició del factor de transcripció HIF-1 un cop ja ha exercit els seus efectes sobre el citoesquelet de microtúbuls. Així doncs, l'objectiu del nostre estudi va ser I) caracteritzar el mecanisme a nivell molecular pel qual el 2ME2 inhibeix el HIF-1 i l'angiogènesis, i II) investigar si hi ha cap relació causa-efecte entre les propietats antiangiogèniques i anti-tubulina del 2ME2. El nostre treball demostra que el 2ME2 inhibeix l'angiogènesis tumoral mitjançant la inhibició dels nivells proteics del factor HIF-1 així com la seva activitat transcripcional, incloent la transcripció del VEGF, en diverses línies cel.lulars. El 2ME2 no indueix la degradació proteica a través del proteosoma ni tampoc redueix els nivells d'ARNm del HIF-1, sinó que més aviat inhibeix la síntesi proteica de novo. Notablement, hem mostrat que el 2ME2 inhibeix el factor HIF-1 amb posterioritat a la disrupció del citoesquelet de microtúbuls aportant sòlides proves que afavoreixen una relació funcional entre els efectes anti-angiogènics i la disrupció dels microtúbuls. Aquests efectes no són una propietat única del 2ME2 sinó que és compartida per altres agents que actuen sobre els microtúbuls, com ara el taxol i la vincristina, suggerint un mecanisme d'acció semblant per a tots aquests agents. Finalment, la nostra investigació demostra per primera vegada que el 2ME2 inhibeix l'angiogènesis en dosis que són eficaces despolimeritzant els microtúbuls in vivo. Així doncs, el nostre treball aporta la primera demostració d'una associació mecanística entre la disrupció del citoesquelet de microtúbuls i la inhibició de l'angiogènesis a través del factor de transcripció HIF-1 i dóna suport a la hipòtesis que els agents que actuen sobre la tubulina inhibeixen tant el creixement tumoral com la vascularització tumoral amb posterioritat a la disrupció del citoesquelet de microtúbuls. Una caracterització més exhaustiva dels senyals que tenen lloc a nivell molecular entre la disrupció del citoesquelet de microtúbuls i l'angiogènesis mediada pel factor de transcripció HIF-1, molt possiblement doni lloc a la identificació de noves dianes per al desenvolupament de noves estratègies terapèutiques. / Angiogenesis, the development of new vessels from preexisting vasculature, is a complex process involving multiple gene products expressed by different cell types, all contributing to an integrated sequence of events. Angiogenesis is required to support tumor growth beyond a certain threshold size. Inherent tumor hypoxia is one of the major factors triggering angiogenesis and consistent with a major role for hypoxia in the overall process, a large number of genes involved in different steps of angiogenesis, including vascular endothelial growth factor (VEGF), are independently responsive to hypoxia. The primary mechanism of tumor response to reduced oxygen levels is via activation of hypoxia inducible-factors-1 (HIF-1). HIF-1 is a heterodimer consisting of two subunits; the labile hypoxic responsive factor, HIF-1, and the non-regulated factor HIF-1β. In the presence of oxygen, HIF-1a is hydroxylated, allowing its interaction with the tumor suppressor protein Von Hippel Lindau (VHL) and its subsequent and rapid degradation by the proteasome. Following hypoxic stabilization, HIF-1 is translocated to the nucleus. There it heterodimerizes with HIF-1 and binds to hypoxia-response elements (HREs), activating the transcription of numerous genes important for cancer survival, metabolic adaptation to hypoxia and angiogenesis. Therefore, the development of agents that inhibit angiogenesis are attractive therapeutic options. Based on successful preclinical data, several anti-angiogenic agents alone or in combination with conventional therapies are now in clinical trials. Among these agents is 2-methoxyestradiol (2ME2), a natural occurring derivative of estradiol, currently undergoing clinical evaluation as an inhibitor of tumor angiogenesis. 2ME2 has been shown to be a well-tolerated small molecule posses antitumor and antiangiogenic activity in different in vivo models. In vitro, 2ME2 has been shown to compete with colchicine for tubulin binding and to disrupt interphase microtubules leading to mitotic arrest and cell death in cultured cancer cells. Furthermore, the ability of microtubule-targeting agents, especially those binding to the colchicine site, has been shown to rapidly shut down existing tumor vasculature. Although several mechanism have been proposed for 2ME2 activity, its mechanism of action still remains unclear. Our hypothesis is 2ME2 inhibits tumor angiogenesis by targeting the HIF pathway downstream of its effects on the microtubule cytoskeleton. Therefore, in this study we seek to I) characterize the molecular mechanism by which 2ME2 inhibits HIF-1 and angiogenesis, and II) Investigate whether there is cause-effect relationship between 2ME2's antiangiogenic and anti-tubulin properties. Our work demonstrated that 2ME2 inhibits tumor angiogenesis by effectively inhibiting HIF-1α levels and transcriptional activity, including transcription of VEGF, in a variety of human cancer cell lines. 2ME2 does not induce proteasomal degradation of HIF-1 nor does it reduces HIF-1 mRNA levels, but rather inhibits the de novo HIF-1 protein synthesis. Notably, we showed that 2ME2 inhibits HIF-1α downstream of disruption of the microtubule cytoskeleton, providing solid proof of a functional relationship between the antitubulin and antiangiogenic effects of 2ME2. These effects of 2ME2 are not unique but rather shared by other microtubule-targeting drugs, such as taxol or vincristine, suggesting a common mechanism of action for all microtubule-targeting drugs. Finally, our findings demonstrate for the first time that 2ME2 inhibits angiogenesis at doses are efficacious disrupting microtubules in vivo. Herein, our work provides the first demonstration of a mechanistic link between disruption of the microtubule cytoskeleton and inhibition of tumor angiogenesis via the HIF-pathway and supports the hypothesis that tubulin-targeting drugs inhibit both tumor cell growth and tumor vascularization following disruption of the microtubule-cytoskeleton. The further characterization of the molecular signal linking the disruption of the microtubule-cytoskeleton with the downregulation of the HIF-mediated angiogenesis, are likely to identify novel targets for the development of new anticancer therapies.

Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.