Made available in DSpace on 2014-08-20T14:37:54Z (GMT). No. of bitstreams: 1 dissertacao_cintia_lidiane_guidoti_aguiar_cunha.pdf: 517290 bytes, checksum: 54cdb2ba4dc72f12759c702f6b1b7cda (MD5) Previous issue date: 2013-07-31 / Neospora caninum is an obligate intracellular protozoan, causes neosporosis and resembles formation by Toxoplasma gondii tissue cysts in their hosts. Humans are not considered intermediate hosts for N. caninum, but its zoonotic potential is questionable, because of the close phylogenetic relationship with T. gondii and the report of a study, which fetuses of nonhuman primates, Rhesus, (Macaca mulatta) infected artificially with lesions similar to those caused by congenital toxoplasmosis. The present study aimed to verify the occurrence of antibodies to N. caninum in humans and its possible association with HIV infection and other risk factors. The presence of antibodies to N. caninum was determined from a sample of 156 HIV-positive patients and 100 HIV-negative individuals of Pelotas, Rio Grande do Sul, Brazil, through the reaction of Indirect Immunofluorescence Assay (IFA), with initial dilution of 1:25. Antibody titers found by IFA ranged between 25 and 800. Samples of 256 human sera analyzed, 47 (18.3%) were positive for N. caninum. Since antibodies to this protozoan were found in 36 HIV-positive patients (23.1%) and in 11 HIV-negative individuals (11%). Multivariate analysis showed that HIV-positive patients who have CD4+ T-lymphocyte count ≤ 350 cells/mm3 have 2.4 times more likely to be seropositive for N. caninum. HIV-negative individuals who have seropositivity for T. gondii have 4.71 times more likely to have antibodies to the agent studied. The results indicate the exposure of humans to N. caninum, with higher prevalence in immunocompromised individuals. / Neospora caninum é um protozoário intracelular obrigatório, causador da neosporose e assemelha-se a Toxoplasma gondii pela formação de cistos teciduais em seus hospedeiros. Os humanos não são considerados hospedeiros intermediários para N. caninum, mas seu potencial zoonótico é discutível, em virtude da proximidade filogenética com T. gondii e do relato de um estudo, onde fetos de primatas não humanos, Rhesus, (Macaca mulatta) infectados artificialmente, apresentaram lesões semelhantes às causadas por toxoplasmose congênita. O presente estudo teve por objetivo verificar a ocorrência de anticorpos para N. caninum em humanos e sua possível associação com a infecção por HIV e outros fatores de risco. A ocorrência de anticorpos para N. caninum foi determinada a partir de uma amostra de 156 pacientes HIV-positivos e 100 de indivíduos HIV-negativos do município de Pelotas, Rio Grande do Sul, Brasil, por meio da Reação de Imunofluorescência Indireta (RIFI), com a diluição inicial de 1:25. Os títulos de anticorpos encontrados através da RIFI variaram entre 25 e 800. Das 256 amostras de soros humanos analisadas, 47 (18,3%) foram positivas para N. caninum. Sendo que anticorpos para esse coccídio foram encontrados em 36 pacientes HIV-positivos (23,1%) e em 11 indivíduos HIV-negativos (11%). A análise multivariada demonstrou que pacientes HIV-positivos que possuem contagem de linfócitos T-CD4+ ≤ 350 células/mm3 possuem 2,4 vezes mais chances de serem soropositivos para N. caninum. Indivíduos HIV-negativos que apresentam soropositividade para T. gondii possuem 4,71 vezes mais chances de apresentarem anticorpos para o agente estudado. Os resultados obtidos indicam a exposição de seres humanos a N. caninum, com prevalência mais elevada em indivíduos imunocomprometidos.

The dog (Canis lupus familiaris) can be infected by a variety of protozoa and may develop clinical signs or remain asymptomatic. Due to the proximity of this kind with the man some protozoa present zoonotic potential, as researchers studied, including Leishmania infantum, Neospora caninum and Toxoplasma gondii. L. infantum, it is responsible for causing visceral leishmaniasis in several species, including the dog and the man with deleterious impacts on public health. The dog is considered the urban reservoir of the parasite, and it is recommended the euthanasia of seropositive, including asymptomatic. N. caninum and T. gondii are widely distributed protozoa. These agents, when affecting dogs, can cause neurological, gastrointestinal, respiratory and muscle disturbs. N. caninum is a protozoan of great economic importance and may cause reproductive problems in farm animals and the dog is the definitive host of this agent. T. gondii is an opportunistic microorganism, a zoonotic potential, with world-occurrence. The dogs as well as humans, are considered intermediate hosts, infection may be more severe in pregnant women and immunocompromised individuals. This study aimed to research anti-Leishmania infantum antibodies, Neospora caninum and Toxoplasma gondii in autopsied dogs; and to determine the occurrence of infection in animals from Agudo, Jaguari, Júlio de Castilhos, Mata, Santa Maria, Santiago, São Martinho da Serra, São Vicente do Sul and Tupanciretã, towns in the central region of Rio Grande do Sul (RS). In addition, there were correlated epidemiological data on sex, age, race, origin and occurrence of these protozoa in the seasons, with the pathological lesions. The animals were necropsied during routine at Pathology Laboratory in the Universidade Federal de Santa Maria, from November 2014 to April 2016. For detection of seropositive dogs, the Indirect Immunofluorescence Antibody Test (IFAT) was performed on stored samples in serum bank Analysis Laboratory in Veterinary Clinics. It analyzed 78 samples, where 53/78 (67.9%) were seropositive, demonstrating the presence of antibodies to one or more of the agents in the population studied. The occurrence of antibodies to L. infantum, N. caninum and T. gondii was 26/78 (33.3%) 29/78 (37.1%) and 34/78 (43.5%) respectively. Mono infections observed in 5/53 (9.4%) of L. infantum, 10/53 (18.8%) to N. caninum and 11/53 (20.7%) T. gondii, while the coinfection appeared in 27/53 (50.9%) of the dogs were detected in 4/53 (7.5%) L. infantum + N. caninum, 8/53 (15.0%) L. infantum + T. gondii, 6/53 (11.3%) N. caninum + T. gondii and 9/53 (16.9%) L. infantum + N. caninum + T. gondii, affecting animals of different ages, without predominance sex or race. There were no pathological characteristic lesions, featuring animals as asymptomatic, indicating a role for these sentinels of dogs these diseases. This study contributed to a better understanding of the epidemiology of protozoa and noted the emergence of visceral leishmaniasis in animals from areas considered harmless. In addition, this work can support the public health services in the adoption of preventive measures, avoiding possible cases of autochthonous leishmaniasis in central RS. / O cão (Canis lupus familiaris) pode ser infectado por uma variedade de protozoários, podendo desenvolver sinais clínicos ou permanecer assintomático. Devido à proximidade desta espécie com o homem e por alguns protozoários apresentarem potencial zoonótico, se realizou um estudo, incluindo Leishmania infantum, Neospora caninum e Toxoplasma gondii. L. infantum, é responsável por causar a leishmaniose visceral em diversas espécies, abrangendo o cão e o homem, com impactos deletérios na Saúde Pública. O cão é considerado o reservatório urbano deste parasita, e recomenda-se a eutanásia dos soropositivos, inclusive os assintomáticos. N. caninum e T. gondii são protozoários de ampla distribuição geográfica. Estes agentes, quando acometem os cães, podem causar distúrbios neurológicos, gastrintestinais, respiratórios e musculares. N. caninum é um protozoário de grande importância econômica, podendo ocasionar problemas reprodutivos em animais de produção e o cão é o hospedeiro definitivo deste agente. T. gondii é um micro-organismo oportunista, de potencial zoonótico, com ocorrência mundial. Os cães, assim como o homem, são considerados hospedeiros intermediários, podendo a infecção ser mais grave em indivíduos imunocomprometidos ou gestantes. Este estudo teve por objetivo pesquisar anticorpos anti-Leishmania infantum, Neospora caninum e Toxoplasma gondii em cães necropsiados; bem como determinar a ocorrência da infecção em animais procedentes de Agudo, Jaguari, Júlio de Castilhos, Mata, Santa Maria, Santiago, São Martinho da Serra, São Vicente do Sul e Tupanciretã, municípios da região central do Rio Grande do Sul (RS). Adicionalmente, correlacionou-se os dados epidemiológicos referentes a sexo, idade, raça, procedência e a ocorrência destes protozoários nas estações do ano, com as lesões anatomopatológicas. Os animais foram necropsiados durante a rotina do Laboratório de Patologia da Universidade Federal de Santa Maria, no período de novembro de 2014 a abril de 2016. Para detecção dos cães sororreagentes, foi realizada a Reação de Imunofluorescência Indireta (RIFI), nas amostras armazenadas no banco de soro do Laboratório de Análises Clínicas Veterinárias. Analisou-se 78 amostras, onde 53/78 (67,9%) apresentaram soropositividade, demonstrando a presença de anticorpos para um ou mais dos agentes na população estudada. A ocorrência de anticorpos para L. infantum, N. caninum e T. gondii foi de 26/78 (33,3%), 29/78 (37,1%) e 34/78 (43,5%) respectivamente. Observou-se mono infecções em 5/53 (9,4%) para L. infantum, 10/53 (18,8%) para N. caninum e 11/53 (20,7%) para T. gondii, enquanto que, as coinfecções apareceram em 27/53 (50,9%) dos cães, sendo detectados em 4/53 (7,5%) L. infantum + N. caninum, 8/53 (15,0%) L. infantum + T. gondii, 6/53 (11,3%) N. caninum + T. gondii e 9/53 (16,9%) L. infantum + N. caninum + T. gondii, acometendo animais de diferentes idades, sem predominância de sexo ou raça. Não verificaram-se lesões anatomopatológicas características, caracterizando os animais como assintomáticos, denotando um papel para estes cães de sentinelas destas enfermidades. Este estudo contribuiu para um maior conhecimento da epidemiologia destas protozooses e observou o surgimento da leishmaniose visceral em animais provenientes de áreas consideradas indenes. Além disso, este trabalho poderá subsidiar os serviços de Saúde Pública na adoção de medidas preventivas, evitando possíveis casos de leishmaniose autóctones na região central do RS.

O presente trabalho teve como objetivo otimizar ensaios sorológicos para serem utilizados na pesquisa de anticorpos dirigidos ao Herpesvírus humano tipo 8 (HHV-8) e com eles explorar grupos de risco para adquirir, transmitir e desenvolver doença relacionada à esta infecção, como o sarcoma de Kaposi (SK). Tomando como base a literatura disponível, as condições do laboratório e a experiência profissional acumulada na Seção de Imunologia do Instituto Adolfo Lutz de São Paulo, foram selecionados e utilizados os ensaios de imunofluorescência indireta (IFI) e Western blot (WB) para a pesquisa de anticorpos dirigidos a antígenos (Ag) de fase latente (LANA) e lítica da infecção por HHV-8. Para a padronização dos testes sorológicos foram utilizadas amostras de soro de 44 pacientes com SK e 21 controles sadios do Laboratório, e para o cálculo de prevalência de infecção HHV-8 em diferentes populações de São Paulo, soros de 3 grupos de indivíduos: - 477 pacientes infectados pelo HIV/AIDS sem SK; - 683 pacientes institucionalizados com deficiência mental e/ou física; - 736 profissionais da área da saúde, sadios. Foram empregados na preparação das lâminas de IFI e nas tiras de WB respectivamente, as células BCBL-1 latentemente infectadas pelo HHV-8 ou estimuladas com forbol éster e o antígeno viral bruto obtido de sobrenadante de lisado das mesmas células. Os resultados obtidos na padronização da IFI-LANA mostraram baixa especificidade do ensaio devendo ser acompanhado pelo teste confirmatório de WB-LANA. Por outro lado, a IFI-Lítico se mostrou altamente sensível e específica, prescindindo do teste confirmatório de WB-Lítico. Este último, devido à complexidade de componentes antigênicos aliado aos diferentes perfis de reatividade de anticorpos encontrados em soros controle positivo e negativo, não se mostrou útil para ser empregado no presente trabalho. Levando em consideração os resultados obtidos na IFI-LANA confirmados pelo WB-LANA e na IFI-Lítico, foi possível determinar a prevalência de infecção HHV-8 no grupo de pacientes infectados pelo HIV/AIDS sem SK que foi de 19,3%, sendo detectados 4,8% de soros positivos para Ag LANA e 17% para Ag Lítico. Neste grupo de pacientes, houve associação estatisticamente significante entre sorologia HHV-8 positiva, sexo masculino e prática homossexual. Baixas prevalências de anticorpos foram detectadas nos pacientes institucionalizados com deficiência mental e/ou física (1,6%) e nos profissionais da área da saúde (1,1%). Anticorpos dirigidos a Ag LANA foram encontrados em 0,6% e 0,95% dos casos, e para Ag Líticos em 1,0% e 0,3% dos casos, respectivamente. Os resultados obtidos mostram que São Paulo não é região endêmica desta infecção viral e que pacientes institucionalizados e profissionais da área da saúde não são grupos de alto risco para adquirir e transmitir o HHV-8; nenhum caso de SK foi relatado neste grupo de indivíduos na ocasião da coleta das amostras de soro. Quanto ao grupo de pacientes infectados pelo HIV/AIDS sem SK, embora 19,3% deles tenham resultado sorologia HHV-8 positiva sendo a maioria para Ag de fase lítica de replicação viral, apenas 2% desenvolveram SK em estudo longitudinal de 5 anos. A explicação encontrada para o baixo número de casos de SK nesta população de indivíduos foi a introdução em 1994, de terapia anti-retroviral em São Paulo, que mudou o curso da infecção HIV e das doenças à ela associadas. Enfim, foi possível implantar ensaios sorológicos de pesquisa de anticorpos específicos, que juntos, apresentam alta sensibilidade e especificidade e que podem ser empregados em levantamentos epidemiológicos e no diagnóstico de infecção HHV-8. / The objective of the present study was to optimize serologic assays to be employed in the search for antibodies against human herpesvirus type 8 (HHV-8) and use them to survey groups at risk to acquire, transmit and develop disease related to this infection, such as Kaposi’s sarcoma (KS). On the basis of the available literature and of the Laboratory conditions and professional experience accumulated in the Immunology Section of the Adolfo Lutz Institute of São Paulo, we selected and used indirect immunofluorescence assay (IFA) and Western blot (WB) for the search of antibodies against antigens (Ag) of the latent (LANA) and lytic phase of HHV-8 infection. Serum samples from 44 patients with KS and from 21 healthy controls from the laboratory were used for the standardization of the serologic tests, and sera from the following 3 groups of individuals were used to calculate the prevalence of HHV-8 infection in different São Paulo populations:- 477 patients infected with HIV/AIDS without KS; - 683 institutionalized patients with mental and/or physical deficiency; - 736 healthy professionals from the health area. For the preparation of IFA slides and WB strips, we respectively used BCBL-1 cells latently infected with HHV-8 or stimulated with phorbol ester and the crude antigen obtained from the supernatant of a lysate of the same cells. The results obtained in the standardization of the IFA-LANA showed low specificity of the assay, which needed to be accompanied by the confirmatory WB-LANA test. In contrast, the IFA-Lytic proved to be highly sensitive and specific, requiring no confirmatory WB-Lytic test. The latter, due to the complexity of the antigenic components joined to the different reactive profiles of the antibodies detected in positive and negative control sera, was not found to be useful for the present study. Considering the results obtained by IFA-LANA confirmed by WB-LANA and those obtained by IFA-Lytic, it was possible to determine the prevalence of HHV-8 infection in the group of HIV-AIDS patients without KS, which was 19.3%, with the detection of 4.8% sera positive for LANA Ag and 17% positive for Lytic Ag. In this group of patients there was a statistically significant association between HHV-8-positive serology, male sex and homosexual practice. Low antibody prevalences were detected in institutionalized patients with mental and/or physical deficiency (1.6%) and in health professionals (1.1%). Antibodies against LANA Ag were detected in 0.6% and 0.95% of cases, and antibodies against Lytic Ag in 1.0% and 0.3% of cases, respectively. The results obtained show that São Paulo is not an endemic region for this viral infection and that institutionalized patients and health professionals are not groups at high risk to acquire and transmit HHV-8; no case of KS was reported by these groups on the occasion of the collection of serum samples. With respect to the patients infected with HIV/AIDS without KS, although 19.3% of them showed HHV-8-positive serology, in most cases for Ag of the lytic phase of viral replication, only 2% developed KS in a 5 year longitudinal study. The small number of KS cases detected in this population is explained by the introduction in 1994 of antiretroviral therapy in São Paulo, which changed the course of HIV infection and of the diseases associated with it. In conclusion, it was possible to set up serologic assays for the detection of specific antibodies which, considered jointly, presented high sensitivity and specificity and which could be used in epidemiologic surveys and in the diagnosis of HHV-8 infection.

Primäres Ziel von ICAP (internationaler Konsens für antinukleäre Antikörpermuster) ist es, einen Konsens zu finden zur Beschreibung der Fluoreszenzmuster, die mit indirekter Immunfluoreszenztechnik auf HEp-2-Zellen erkannt werden können. 28 Muster (14 Kern-, 9 zytoplasmatische und 5 mitotische Muster) wurden bisher definiert. Neben der Musterbeschreibung wurden alle Muster auch mit AC-Nummern gekennzeichnet, um eine von der Sprache unabhängige Vergleichbarkeit zu gewährleisten. Alle ICAP-Ergebnisse können von der ICAP-Internetseite (www.anapatterns.org) abgerufen werden. ICAP ist ein fortlaufender Prozess. Das nächste und 4. ICAP-Treffen wird im September 2017 im Rahmen des 13. Autoantikörpersymposiums in Dresden stattfinden (www.gfid-ev.de). Anstehende ICAP-Aufgaben sind die Ergänzung der Fluoreszenzmuster, die Erweiterung der Bildersammlung und die genauere Beschreibung der klinischen Bedeutung einzelner Muster.

The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.

Nuclear receptors constitute a large family of transcription factors that are powerful regulators of animal tissue metabolism, homeostasis, tissue maintenance and development. They are particularly attractive for their ability to respond to the binding of hormones, metabolites, xenobiotics and artificially prepared molecules and transmit the interaction with these small lipophylic molecules to specific regulatory potential. In search for nuclear receptors that are likely to be critical for neural tissues in invertebrates and conserved during the evolution of animals, we have identified a close homologue of vertebrate TLX in a planarian Schmidtea mediterranea. Planaria represent very promising biological model systems for studies on tissue maintenance and regeneration. Planaria are able to resorb their tissues and use them as sources of energy during fasting and they re-build their bodies from neoblasts when food is plentiful. Our search in Schmidtea mediterranea's publicly accessible genome sequencing data indicated that planarian genome contains at least one gene with a high degree of similarity to vertebrate TLX. We cloned full length CDS (coding DNA sequence of cDNA) and characterized the gene functionally. This showed that the planarian and vertebrate NR2E1 are highly similar...

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18346号 / 農博第2071号 / 新制||農||1024(附属図書館) / 学位論文||H26||N4853(農学部図書室) / 31204 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 栗原 達夫, 教授 植田 充美, 教授 小川 順 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Indiana University-Purdue University Indianapolis (IUPUI) / SIMPL is a transcriptional co-activator that alters the activity of transcription factor, NF-κB. In response to pathogens, cytokines such as Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) signal through the IL-1 and TNF-α receptors, respectively, which are found on various cell types. Activation of these receptors can result in the nuclear localization of NF-κB where it enables the transcription of several different genes key in the innate immune response. Endogenous co-localization of the SIMPL protein with NF-κB in response to these same cytokine signals has yet to be demonstrated. Polyclonal antibody generated against a truncated version of the SIMPL protein was purified from the sera obtained from immunized rabbits using affinity chromatography. The antibody was found to have a high specificity for both the native and denatured form of the protein as demonstrated by the lack of nonspecific bands observed in immunoprecipitations and Western blotting. The antibody was utilized in immunofluorescence experiments on mouse endothelial cells that were either unstimulated or were stimulated (IL-1 or TNF-α). In the absence of cytokine, SIMPL was localized in both the cytoplasm and the nucleus as opposed to NF-κB which was almost exclusively localized in the cytoplasm. In the presence of IL-1, the concentration of SIMPL in the nucleus was increased, and in the presence of TNF-α, the concentration of SIMPL in the nucleus was even greater. Results of this study identified future routes for SIMPL antibody isolation as well as to demonstrate that endogenous SIMPL protein nuclear localization may not be solely dependent upon TNF-α signaling.

Feline morbilliviruses (FeMV) are fairly newly discovered paramyxoviruses found in cats. The first description indicated an association with widely distributed chronic kidney disease (CKD) in the host species. In various studies, a global prevalence and a further genotype, designated FeMV-2, and the involvement of other organ systems in infected individuals were shown. Using an immunofluorescence assay, we detected an overall seroprevalence of FeMV in almost half of the cats investigated (n = 380), with a significantly increased proportion in younger animals. In comparison to European Shorthair cats, the rate of seropositivity is higher in pedigree cats. Regardless of the breed, FeMV infection was associated with increased blood creatinine concentrations, suggesting an association with CKD. Further analysis indicated that this association was the strongest in animals having high IFA titers against FeMV-2. In addition, a significant association between FeMV-positive status and the prevalence of feline lower urinary tract disease (FLUTD, or idiopathic cystitis) was detected. This association was dominated by cats having antibodies against FeMV-1 only. To further evaluate the positive correlation between FeMV seroprevalence and CKD as well as FLUTD, consideration of additional clinical characteristics and laboratory parameters is warranted, and controlled infection studies with both FeMV genotypes are necessary. Clinicians should, however, be aware of a possible link between renal and lower urinary tract disease and FeMV infections.

Adaptor proteins, like Tollip and Tom1, facilitate cellular cargo sorting through their ubiquitin-binding domains. Tollip and Tom1 bind to each other through their TBD and GAT domains, respectively, whereas Tollip interacts with phosphatidylinositol-3-phosphate (PtdIns(3)P)-containing endosomal membranes. Tom1 and Tollip interaction and association with endosomes is proposed to be involved in the lysosomal degradation of polyubiquitinated cargo. Through cellular, biochemical, and biophysical techniques, we have further characterized the association of Tom1 with Tollip. Mutations in the binding interface of the Tom1 GAT and Tollip TBD complex leads to a subcellular mis-localization of both proteins, indicating that Tom1 may serve to direct Tollip to specific cellular pathways. It was determined that Tom1 inhibits the binding of Tollip to PtdIns(3)P and inhibition was reversed when mutations in the binding interface of the Tom1 GAT and Tollip TBD were present. Furthermore, it was established that, upon the binding of Tollip TBD to Tom1 GAT, ubiquitin is inhibited from binding to Tom1 GAT. It was also demonstrated that Tom1 GAT, but not Tollip TBD, can weakly bind to PtdIns(3)P. Consequently, we propose that association of Tom1 may serve to direct Tollip for involvement in specific cell signaling pathways. Gaining insight into the function of Tom1 and Tollip may lead to their use as therapeutic targets for increasing the efficiency of cargo trafficking and also for patients recovering from various cardiac injuries. / Master of Science