Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / "May 1998." Typescript. Vita. Includes bibliographical references (leaves 138-147). Also available on the Internet.

Thesis (Ph.D. in Molecular Biology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 123-140). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [63]-80).

Thesis (M.Sc.)--Memorial University of Newfoundland, 1997. / Restricted until June 2000. Bibliography: leaves 230-274.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Embargoed. Vita. Bibliography: 92-104.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Physiology and Biophysics. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Diss. (sammanfattning) Göteborg : Univ. , 2009. / Härtill 3 uppsatser.

Η αθηρωματική νόσος είναι η κύρια αιτία καρδιαγγειακών νοσημάτων (CVD). Σύμφωνα με τον WHO το 2004 οι θάνατοι λόγω CVD ήταν 17.1 εκατομμύρια, το 29% των θανάτων παγκοσμίως. Η παθογένεια της νόσου είναι πολυπαραγοντική και οφείλεται σε περιβαλλοντικά και γενετικά αίτια, ένα από τα οποία είναι οι λιπιδαιμικές διαταραχές. Μελέτες τόσο in vitro όσο και in vivo σε ανθρώπους και πειραματόζωα καταδεικνύουν την απολιποπρωτεΐνη Ε (ApoE) ως κομβικό μόριο στη μεταφορά και το μεταβολισμό των λιποπρωτεϊνών, οι οποίες αποτελούν τα μεταφορικά μέσα των λιπιδίων. Η ΑpoE εκφράζεται σε ποικίλους ιστούς, όπως ο λιπώδης ιστός, τα ενδοθηλιακά κύτταρα, τα μακροφάγα και ο εγκέφαλος, αν και η κύρια θέση παραγωγής της είναι το ήπαρ. Στις δράσεις της ΑpoE περιλαμβάνονται η ηπατική πρόσληψη των λιποπρωτεϊνών, η ενεργοποίηση ενζύμων που συμμετέχουν στον μεταβολισμό των λιποπρωτεϊνών (LCAT, CETP, HL) η μεταφορά χοληστερόλης από περιφερικούς ιστούς στο ήπαρ με στόχο την κάθαρση και τελικώς τη ρύθμιση της ομοιόστασης του ισοζυγίου της χοληστερόλης στο αίμα. Η απομάκρυνση VLDL και υπολειμμάτων χυλομικρών από την κυκλοφορία μέσω της αγρίου τύπου (wt) ΑpoE προϋποθέτει την ύπαρξη λειτουργικών υποδοχέων LDLr. Στους ανθρώπους μεταλλάξεις ή πλήρης έλλειψη έκφρασης του LDLr οδηγεί στη εμφάνιση Οικογενής υπερχοληστερολαιμίας (FH). Στην περίπτωση της ομόζυγης Οικογενής υπερχοληστερολαιμίας (HoFH) οι ήδη υπάρχουσες φαρμακολογικές προσεγγίσεις είναι αναποτελεσματικές, με συνέπεια οι ασθενείς να καταλήγουν πρόωρα. Παρά τις ωφέλιμες δράσεις της wt ApoE στο μεταβολισμό των λιποπρωτεϊνών, η θεραπευτική της αξία είναι περιορισμένη καθώς σε συγκεντρώσεις άνω των φυσιολογικών επιπέδων στο πλάσμα επάγει συνδυαστική υπερλιπιδαιμία. Η διερεύνηση της δομής και των λειτουργικών θέσεων της ΑpoΕ οδήγησε στην κατασκευή μιας τεχνητά μεταλλαγμένης μορφής, της ΑpoE4mut1 , η οποία όχι μόνο δεν προκαλεί διαταραχή λιπιδίων αλλά έχει και βελτιωμένες δράσεις σε σχέση με την wt ΑpoE. Η έρευνα που αναλύεται στην εργασία αυτή ξεκίνησε με σκοπό να μελετηθεί η αναγκαιότητα έκφρασης λειτουργικού υποδοχεά LDLr για την εκδήλωση των βελτιωμένων βιολογικών δράσεων της ΑpoE4mut1. Συγκεκριμένα, σε υπερχοληστερολαιμικά ποντίκια με ταυτόχρονη έλλειψη στην ΑpoE και τον LDLr (ApoE-/- x LDLr-/-) χορήγηση της μεταλλαγμένης μορφής ΑpoE4mut1 μέσω αδενοϊών οδήγησε σε μείωση των επιπέδων χοληστερόλης στο αίμα τους. Το γεγονός αυτό καταδεικνύει μια νέα ιδιότητα της ΑpoE4mut1 πολλά υποσχόμενη όσον αφορά στην ανακάλυψη νέων θεραπευτικών κατευθύνσεων για την ομόζυγη οικογενή υπερχοληστερολαιμία (ΗoFH). / Atherosclerosis is a focal disease that constitutes the main cause of coronary heart disease (CHD) and cardiovascular diseases (CVD). According to WHO an estimated 17.1 million people died from CVDs in 2004, representing 29% of all global deaths. The initial formation and progression of atheromatic lesions involves a complex interplay of both genetic and environmental factors, such as dyslipidemias. In vitro and in vivo studies, both in animal models and humans, have established that apolipoprotein E has a key role in the metabolism of lipoproteins, which are the main transport vehicles of the lipids in the circulation. ApoE is mainly synthesized by the liver and secondary by other tissues, such as fat tissue, macrophages, brain. The protein is involved in the efficient hepatic uptake of lipoprotein particles, the activation of enzymes, such as LCAT, CETP, which participate to metabolic pathways of lipoproteins, and the stimulation of reverse cholesterol transport from peripheral tissues to the liver. Therefore, ApoE is capable of regulating cholesterol homeostasis in plasma. The expression of functional LDLr is required by wild type ApoE, in order to perform the clearance of lipoprotein particles. In humans mutations or total deficiency in LDLr result in a disease called Familial Hypercholesterolemia (FH). Homozygote patients with FH (HoFH) do not benefit from the conventional therapies and die prematurely. Despite the central role of wt ApoE in the metabolism of lipoprotein particles, its therapeutic value is reduced due to the limitation that at concentrations higher than physiological, plasma ApoE induces combined hyperlipidemia. Studies on the structure-function relationship of the protein resulted in the generation of a mutant variant ApoE4mut1, which has improved functions regarding wt ApoE4 and does not induce hypertriglyceridemia. The present study was initiated in order to determine whether the improved functions of ApoE4mut1 require the expression of LDLr. The results demonstrated new possible interventions for the treatment of HoFH. In particular, hypercholesterolemic mice with deficiency both in ApoE and LDLr genes (ApoE-/- x LDLr-/-), which expressed through adenovirusmediated gene transfer the mutant ApoE4mut1, showed a decrease in the cholesterol levels. This finding may lead to important therapeutic applications as a new treatment for HoFH when gene therapy becomes a reality in the future.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-07-26T12:55:35Z No. of bitstreams: 1 Leonor Fernandes Teixeira Amaral Remodelamento...2015.pdf: 447268 bytes, checksum: f7454eb0efdd04147e5c7a0370bd8d82 (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-07-26T13:04:59Z (GMT) No. of bitstreams: 1 Leonor Fernandes Teixeira Amaral Remodelamento...2015.pdf: 447268 bytes, checksum: f7454eb0efdd04147e5c7a0370bd8d82 (MD5) / Made available in DSpace on 2016-07-26T13:04:59Z (GMT). No. of bitstreams: 1 Leonor Fernandes Teixeira Amaral Remodelamento...2015.pdf: 447268 bytes, checksum: f7454eb0efdd04147e5c7a0370bd8d82 (MD5) Previous issue date: 2015-08-28 / Fundação Gonçalo Moniz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / INTRODUÇÃO: as doenças cardiovasculares acometem milhares de pessoas no mundo, sendo a doença aterosclerótica a de maior morbimortalidade. Além disso, a aterosclerose pode manifestar-se precocemente dada a presença de dislipidemias, processos inflamatórios e alterações metabólicas como a diabetes. OBJETIVO: avaliar se existem diferenças no remodelamento da HDL e atividade antioxidante entre pacientes diabéticos e não diabéticos com doença aterosclerótica. Ainda, identificar, quantificar e estimar biomarcadores relacionados ao remodelamento de partículas lipoprotéicas e ao risco cardiovascular em função da concentração de colesterol na HDL, colesterol livre total, LDL-C, apoB, apoA-I, atividade da paraoxonase 1 (PON1), razões de risco como TG/HDL-C, LDL-C/ApoB, HDL-C/apoA-I, PON1/apoA-I, apoA-I/ApoB e tamanho estimado de partículas de HDL, LDL, glicemia, insulina e HbA1c. MÉTODOS: foram selecionados por conveniência 69 pacientes do sexo masculino, entre 18 e 75 anos, oriundos da enfermaria de cardiologia do Hospital Ana Neri, subdivididos em dois subgrupos: diabéticos e não diabéticos, ambos, com doença aterosclerótica coronária. Foram utilizadas metodologias enzimáticas, imunoturbidimétricas e nefelometricas nesse estudo. RESULTADOS: dos achados da comparação direta entre os grupos apenas a glicemia de jejum foi significativamente diferente (Teste t; p<0,05). Embora não significante o valor do colesterol não esterificado (CL) foi, em média, quatro vezes maior nos diabéticos quando comparado aos não diabéticos. A análise de correlação linear mostrou achados importantes do ponto de vista fisiológico, como correlação positiva entre CL e HDL-C (r=0,617; p<0,01083) e razão apoA-I/apoB e insulina (r=0,489; p<0,02095) nos diabéticos, e correlação negativa entre PON1/apoA-I com CL (r=-0,499; p<0,0065) e HDL-C com HbA1c (r=-0,444; p<0,0324) nos pacientes não diabéticos. CONCLUSÃO: Os achados desse estudo mostram que o cálculo das razões utilizadas para a análise de risco cardiovascular foram importantes indicadores quando correlacionados com marcadores séricos sugestivos de risco cardiovascular na população masculina diabética deste estudo. / Introduction: cardiovascular diseases affect thousands of people around the world, and atherosclerotic disease is the one with the greatest morbidity and mortality. Furthermore, atherosclerosis may manifest early by the presence of dyslipidemia, inflammatory processes and metabolic disorders such as diabetes. Objective: to assess whether there are differences between HDL remodeling and antioxidant activity from diabetic and nondiabetic patients with coronary artery disease. Also, identify, quantify and evaluate biomarkers related to lipoprotein particles remodeling and cardiovascular risk depending on HDL cholesterol concentration, total free cholesterol, LDL-C, apoB, apoA-I, paraoxonase activity 1 (PON1), and risk ratios like TG/HDL-C, LDL-C/ApoB, HDLC/ apoA-I, PON1/apoA-I, apoA-I/ApoB, HDL and LDL estimated particles size, glucose, insulin and HbA1c. Methods: we selected by convenience 69 male patients between 18 and 75 years, from the Cardiology Unit of Hospital Ana Neri, they were subdivided into two groups: diabetic and non-diabetic patients, both with coronary atherosclerosis. In these study were used enzymatic, immunoturbidimetric and nephelometric methodologies. Results: From the findings of the direct comparison between groups only fasting glucose was significantly different (t test; p <0.05). Although not significant, the value of non-esterified cholesterol (CL) was on average, four times higher in diabetics when compared to non-diabetics. Linear correlation analysis showed significant findings, from a physiological point of view, as positive correlation between CL and HDL-C (r = 0.617, p <0.01083) and apoA-I ratio/apoB and insulin (r = 0.489, p <0.02095) in diabetics, and negative correlation between PON1/apoA-I with CL (r = -0.499; p <0.0065) and HDL-C with HbA1c (r = -0.444; p <0.0324) in patients non-diabetic. Conclusion: the findings shows that the calculated ratio´s used for cardiovascular risk analysis were important indicators when correlated to serum markers suggestive of cardiovascular risk in the study diabetic male population.

Orientador: Regina Kiomi Takahira / Banca: Michiko Sakate / Banca: Raimundo Souza Lopes / Banca: Mara Regina Stipp Balarin / Banca: Nayra Xavier de Alencar / Resumo: A doença hepática é frequentemente incluída como diagnóstico diferencial dos casos atendidos na clínica médica de pequenos animais. Os cães com suspeita de doença hepática podem apresentar sinais clínicos específicos e/ou inespecíficos e possuir característica de doença aguda ou crônica. Os exames laboratoriais auxiliam na identificação de lesão dos hepatócitos, colestase ou perda da função hepática, o perfil hepático pode ser avaliado por meio de diversos testes, inclusive avaliando o metabolismo de lipídeos e lipoproteínas, pois uma das funções do fígado é o metabolismo de lipídeos. O presente trabalho teve por objetivo avaliar os perfis hematológico, hepático, lipídico e lipoprotéico de cães com doença hepática e também comparar diferentes técnicas de análise. Foram utilizados 34 cães, adultos, machos e fêmeas, divididos em dois grupos, sendo: Grupo I (controle) e Grupo II (hepatopatia), e submetidos a jejum alimentar superior a 12 horas para a realização dos exames do perfil lipídico e lipoprotéico. Na avaliação hematológica do Grupo II (hepatopatia) observou-se anemia e discreta trombocitopenia e neutrofilia; o perfil hepático demonstrou presença de lesão ativa em hepatócitos, associado a colestase e ausência de insuficiência hepática; o perfil lipídico revelou colesterol sérico normal e aumento do valor de triglicerídeos e no perfil lipoprotéico observou-se diminuição de HDL e aumento de Lp(a), VLDL e LDL. A avaliação do perfil lipoprotéico é mais sensível, que o perfil lipídico na detecção de alterações no metabolismo de lipídeos e também é mais precoce que a albumina na detecção da disfunção hepática em cães. Para a química seca com sangue total fresco, existe a necessidade de valores de referência específicos, e não possui a sensibilidade adequada na mensuração do nível sérico... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Liver disease is frequently included as a differential diagnosis of clinical cases attended at small animals clinics. Dogs presenting a suspected case of liver disease can show specific and/or unspecific clinical signs and reveal characteristics of acute or chronic disease. The laboratory profile is useful in the identification of hepatocelular lesions, colestasis or loss of the hepatic function; the hepatic profile can be composed by several tests, including the evaluation of the metabolism of lipids and lipoproteins, since one of the liver functions is the metabolism of lipids. The objective of the present work was to evaluate the lipids and lipoproteins profile of dogs with liver disease and also to compare different techniques of analysis. Thirty-four adult dogs, males and females were divided in two groups: Group I (control) and Group II (liver disease), and were submitted to a 12 hours fasting period previously to the lipid and lipoprotein profiles. In the Group II (liver disease) hematological evaluation revealed anemia, mild thrombocytopenia and neutrophilia; the hepatic profile demonstrated lesion in hepatocytes, associated with colestasis and absence of hepatic insufficiency; the profile lipid revealed cholesterol normal and increase of the triglycerides value and in the profile lipoprotein, it was observed decrease of HDL and increase of Lp(a), VLDL and LDL. The evaluation of the lipoprotein profile is more sensitive, that the lipid profile in the detection of alterations in the lipids metabolism and it is also more precocious than the albumin in the detection of the hepatic dysfunction in dogs. For the chemistry dry with fresh total blood, the need of specific reference values exists, and it doesn't possess the appropriate sensibility in the measurable of the level serum triglycerides. The lipoproteins electrophoresis in agarose gel is more sensitive than the serum biochemistry. / Doutor