INTRODUÇÃO: A degeneração macular relacionada à idade (DMRI) é a principal causa de perda de visão irreversível e cegueira mundialmente. A perda da visão central interfere nas atividades de vida diária, como o reconhecimento facial, leitura e escrita, direção de veículos automotores e em atividades funcionais e de lazer. Esta perda de visão relaciona-se também com o desencadeamento de quadros de ansiedade e depressão. Este estudo avaliou a qualidade de vida visual em pacientes com degeneração macular relacionada à idade neovascular por meio do questionário de função visual 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). MÉTODOS: Estudo clínico observacional de 87 pacientes de ambos os sexos, com idade >= 50 anos e com o diagnóstico de DMRI neovascular unilateral ou bilateral. Todos os pacientes responderam ao questionário de função visual NEI VFQ- 25 no final do tratamento em regime Tratar e Estender ou PrONTO, com as drogas antiangiogênicas ranibizumabe ou aflibercepte. RESULTADOS: A idade dos pacientes foi a variável que menos influenciou a qualidade de vida visual dos pacientes. O gênero teve uma influência um pouco maior que a idade, no entanto, a lateralidade da doença demonstrou maior influência na qualidade de vida visual, comparada ao gênero e idade dos pacientes e foi significante para oito dos 12 domínios do questionário de função visual NEI VFQ-25. Os pacientes com acometimento bilateral tiveram pontuações mais baixas que os com doença unilateral em todos os domínios do questionário. A acuidade visual corrigida (AVc) foi a variável que apresentou o maior número de domínios com valores significantes e, portanto, foi a variável que mais se correlacionou com a qualidade de vida visual. A AVc do melhor olho (MO) foi significante para a maioria dos domínios relacionados com a visão, ao contrário do pior olho (PO) que não foi significante para nenhum domínio do questionário. CONCLUSÃO: Todas as variáveis testadas afetaram a qualidade de vida visual dos pacientes, onde a lateralidade teve uma maior influência, seguida pela idade e sexo dos pacientes. Na tomada de decisão para o tratamento de pacientes com DMRI neovascular, pelo menos para esta população, a manutenção da AVc do MO >= 0,5 (escala decimal de Snellen) foi essencial para a manutenção de boa qualidade de vida visual, independente da AVc do PO, que não teve efeito significante em nenhum domínio do questionário de função visual NEI VFQ-25 / INTRODUCTION: The neovascular age-related macular degeneration (AMD) is the main cause of irreversible loss of vision and blindness woldwide. The loss of the central visual field interferes on daily activities such as facial recognition, reading and writing, driving as well as functional and leasure activities. This loss of vision may also increases anxiety and depression for this age group. To evaluate the impact of neovascular AMD on the visual quality of life of patients using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). METHODS: This was an observational clinical, with 87 patients of both genders, with age >= 50 years and a clinical diagnosis of unilateral or bilateral neovascular age related macular degeneration. All patients answered the visual functioning questionaire NEI VFQ-25 at the end of the treatment with the Treat and Extend or PrONTO regimen using antiangiogenic drugs ranibizumab or aflibercept. RESULTS: The age of patients was the variable with the lower influence on the quality of life of the patients. Gender had an influence slightly higher then the age, however, the laterality of the disease had the highest influence on the quality of life, compared with age and gender, and was significant for 8 of the 12 domains of the visual functioning questionaire NEI VFQ-25. The patients with bilateral age-related macular degeneration had lower scores than patients with unilateral disease for all domains of the questionaire. Visual acuity was the variable with the higher number of domains with significant values, and therefore the variable with the higher correlation with the quality of life. The visual acuity of the best eye (BE) was significant for most of the vision related domains, in opposition the the visual acuity of the worst eye (WE) which was not significant for any domain of the questionaire. CONCLUSION: All variables tested affected the visual quality of life, where the laterality of the disease had the highest influence, followed by the age and gender of the patients. The decision process for the treatment of patients with neovascular AMD, at least for this population, keeping the visual acuity of the BE >= 0,5 (Snellen\'s decimal scale) was essential to maintain a long term quality of life, despite the visual acuity of the worst eye, that had no significant effect on any domain of the visual functioning quaestionaire NEI VFQ-25

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-08-28T13:10:36Z No. of bitstreams: 0 / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-30T14:36:00Z (GMT) No. of bitstreams: 0 / Made available in DSpace on 2017-08-30T14:36:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-08-26 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / O soro de leite, proveniente da fabricação de queijos diversos, ainda é um grave problema na indústria de laticínios, tendo em vista que seu descarte tem um impacto negativo no meio ambiente e seu tratamento por vezes se torna economicamente inviável. Diante do exposto, o presente trabalho visa produzir uma bebida láctea acidificada, aromatizada, carbonatada e enriquecida com luteína. A fim de aproveitar este produto disponível na indústria láctea, altamente rico em proteínas, vitaminas e minerais, para a fabricação de uma bebida refrescante, adicionada de dióxido de carbono (CO2), e considerada de possível uso funcional, uma vez que foi adicionado o extrato de luteína. O soro para a fabricação da bebida foi obtido a partir da fabricação do queijo Minas Frescal. O produto foi produzido em 4 repetições e cada repetição foi analisada ao longo do período máximo de 120 dias, sendo aplicados dois tratamentos: sob refrigeração e em temperatura ambiente. O produto apresentou estabilidade microbiológica durante todo o tempo de estocagem (120 dias) nas diferentes temperaturas, não apresentando contagem de microrganismos, confirmando a eficácia das barreiras microbiológicas aplicadas (pH, CO2 e tratamento térmico). As análises sensoriais demonstraram que o produto apresentou boa aceitação e que o mais aceito foi aquele armazenado sob refrigeração, bem como a aceitação se mostrou inversamente proporcional ao tempo de estocagem, sendo que a viscosidade aumentou ligeiramente em função do tempo de estocagem, para o produto conservado sob refrigeração. O extrato de luteína foi adicionado ao produto aumentando sua atividade antioxidante, o que pode auxiliar no fortalecimento do tecido formador da mácula ocular, prevenindo sua degeneração e aumentando a sua resistência contra doenças relacionadas. O produto apresentou teor de proteínas preconizado pela legislação além de gordura, minerais e elevada atividade antioxidante devido à adição de luteína, ou seja, o produto mostrou-se nutricionalmente superior se comparada à outras bebidas carbonatadas (como refrigerantes). A bebida láctea desenvolvida possui baixo custo de fabricação podendo agregar valor ao soro e permitindo o seu uso adequado e sustentável por parte das indústrias de laticínios. / The whey, from the production of various cheeses, it is still a serious problem in the dairy industry, with a view to its disposal have a negative impact on the environment and treatment sometimes becomes uneconomic. Given the above, this work aims to produce an acidified milk drink, flavored, carbonated and enriched with lutein. In order to make this product available in the dairy industry, with protein, vitamins and minerals, for the manufacture of a refreshing drink, due to the added CO2 and considered functional use, once it has been added lutein extract. The whey for the manufacture of the drink was obtained from the manufacture of Minas Frescal cheese. The product was produced in 4 replicates and each replicate was analyzed over a maximum period of 120 days, the two treatments being applied: under refrigeration and at room temperature. The product had physical chemical and microbiological stability during the storage time (120 days) at different temperatures, showing no count of microorganisms, confirming the effectiveness of the microbiological barrier (pH, CO2 and heat treatment). The sensory analysis showed that the product had good acceptance and that the most widely accepted is the one stored under refrigeration, and the acceptance was inversely proportional to the storage time, and the viscosity increased slightly as a function of storage time for the product kept under refrigeration. The lutein extract was added to the product in order to increase its antioxidant activity, which can help strengthen the forming fabric of the eye macula, preventing degeneration and increasing their resistance against diseases. The product showed levels of protein according to the legislation, fat and minerals, in addition to high antioxidant activity due to the addition of lutein. The product was found to be nutritionally superior if compared to other carbonated drinks (such as soda). The developed milk drink has low manufacturing cost and can add value to the whey and allowing its proper and sustainable use by the dairy industry.

La Dégénérescence Maculaire Liée à l'Age (DMLA) constitue dans les pays industrialisés la 1ère cause de cécité chez les personnes de plus de 50 ans, et représente un enjeu majeur de santé publique d'autant plus important que le vieillissement de la population ne fait que s'accroître. La forme atrophique de cette maladie, pour laquelle il n'existe actuellement aucun traitement, est notamment caractérisée par une inflammation sous-rétinienne associée une dégénérescence des photorécepteurs, et conduit à une perte progressive de la vision centrale pouvant aller jusqu'à la cécité. Nos résultats montrent qu'au stade précoce de la maladie (MLA) on peut déjà observer de nombreux phagocytes mononucléaires (PM) dans l'espace sous-rétinien, en contact avec les drusen. Ces PM expriment de l'apolipoprotéine E (APOE), protéine impliquée dans l'homéostasie lipidique et la régulation de réponses inflammatoires, qui est retrouvée dans les drusen des patients atteints de DMLA, et dont le variant génétique APOε2 est associé à un risque élevé de développer une DMLA. Grâce à l'utilisation de souris Cx3cr1GFP/GFP déficientes en CX3CR1, un récepteur de chimiokine, et de souris humanisées APOε2, les travaux présentés ici démontrent que l'APOE exerce un rôle pro-inflammatoire conduisant de manière dose-dépendante à une altération du privilège immun sous-rétinien. Cet environnement immunosuppresseur est dépendant du FasL exprimé par l'épithélium pigmentaire rétinien (EPR), et empêche en condition physiologique la présence de cellules inflammatoires dans la rétine externe. Nos résultats montrent que l’APOE stimule de manière autocrine la sécrétion d’IL-6 par les PM, possiblement par un mécanisme impliquant une activation des Toll-like receptors (TLR) et de leur corécepteur CD36. Nous montrons que l’IL-6 inhibe l’expression de FasL sur l’EPR et altère sa capacité de clairance sous-rétinienne, ce qui facilite la survie des PM infiltrants au contact des photorécepteurs. La persistance de cette inflammation pathologique dans la rétine externe conduit au cours du vieillissement à une dégénérescence des photorécepteurs, phénomène qui peut est inhibé chez des souris déficientes en APOE. Ensemble, ces résultats permettent d’apporter une explication inédite au risque élevé de développer une DMLA pour les porteurs de l’allèle APOε2, et pourrait ouvrir la voie vers de nouvelles perspectives thérapeutiques. / Age-related Macular Degeneration (AMD) is the first cause of blindness in people over 50 year old in industrialized countries, and represents a major public health concern as the population of elderly is more and more increasing. The atrophic form of the disease, for which there is currently no treatment available, is characterized by subretinal inflammation associated with photoreceptor degeneration and leads to a progressive loss of central vision that can lead to blindness. Our results show many mononuclear phagocytes (MP) are already present at the early stage of the disease (MLA), in the subretinal space and in apposition with drusen. These PM express apolipoprotein E (APOE), a protein involved in lipid homeostasis and the regulation of inflammatory responses, which is found in drusen in patients with AMD, and whose genetic APOε2 variant is associated with a high risk of developing AMD. Using Cx3cr1GFP/GFP mice (deficient in CX3CR1, a chemokine receptor) and humanized APOε2 mice, the work presented herein demonstrates that APOE exerts a pro-inflammatory role leading to a dose-dependent alteration of the subretinal immune privilege. This immunosuppressive environment is dependent upon FasL expression by the retinal pigment epithelium (RPE), and prevents in physiological condition the presence of inflammatory cells in the outer retina. Our results show that APOE stimulates in an autocrine fashion the secretion of IL -6 by PM, possibly through a mechanism involving activation of Toll- like receptors (TLR) and their coreceptor CD36. We show that IL-6 inhibits the expression of FasL on the RPE and impairs its subretinal clearance capacity, which facilitates the survival of infiltrating PM in contact with photoreceptors. The persistence of a pathological inflammation in the outer retina leads to age-dependent photoreceptor degeneration, which can be inhibited in APOE-deficient mice. Taken together, these results provide novel rationale for the higher risk of developing AMD for APOε2allele carriers, and could allow the emergence of new therapeutic perspectives.

Background: Olfactory dysfunction is a common symptom of many neurodegenerative diseases, and age-related macular degeneration (AMD) is a late-onset neurodegenerative disease. Objective: Thus, the aim of this study was to investigate olfactory functions in patients with AMD. Methods: A total of 69 subjects with AMD and 69 age- and sex-matched healthy controls were enrolled. After a complete ophthalmic evaluation, the AMD patients were subclassified as earlyand late-stage AMD. Psychophysical testing of olfactory function was performed using the validated Sniffin’ Sticks test. Results: This study was carried out in 138 subjects, with a mean age of 74.3 ± 8.9 years (range 51–89). The current investigation showed the following two major findings: (1) patients with AMD had decreased olfactory abilities, especially in odor discrimination and odor identification, even at early stages compared to controls, whereas patients had decreased olfactory abilities in all subtasks of olfactory testings in advanced stages of AMD disease, and (2) as the visual acuity of AMD patients decreased, the olfactory abilities of these patients worsened. Conclusion: This study demonstrated that AMD had significant negative effects on all orthonasal olfactory tasks, particularly in advanced stages. Similar to other neurodegenerative diseases, odor discrimination and identification seemed to be more affected than odor detection threshold tasks.

PURPOSE: Retinal and choroidal ischemic retinopathies such as retinal-vein occlusion (RVO), diabetic retinopathy (DR), and age-related macular degeneration (AMD) are ocular diseases caused by abnormal changes in the microvasculature. The ischemia can lead to macular edema or neovascularization, which can affect vision. Intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) can help to reduce macular edema and improve visual acuity. Lost to follow-up (LTFU) after anti-VEGF injections increases the risk of vision loss in patients with RVO, DR, and AMD. METHODS: Patients scheduled for an IVI of anti-VEGF between September 2009 and September 2019 with either RVO, DR, or AMD were included in the analysis. LTFU was defined as missing an appointment without another evaluation for at least one interval exceeding 180 days. All patients were seen by a single provider at an urban, hospital-based, single-site retina practice in Boston, MA. RESULTS: Among the 698 patients (mean [SD] age, 70.23 [14.2] years; 373 [53.4%] female) identified as receiving an IVI, 121 (17.3%) were LTFU. Age was not found to be statistically different between the LTFU and not LTFU groups (mean difference, -1.67; 95% CI, -4.66¬–1.32; P=.27). Odds of LTFU was lower among patients with AMD (odds ratio [OR], 0.57; 95% CI, 0.36-0.92; P=.02). Odds of LTFU was greater among patients with Medicaid insurance (OR, 2.31; 95% CI, 1.22-4.33; P=.01), compared with patients with Medicare insurance. A trend towards higher risk of LTFU was seen in patients with DR (OR, 1.42; 95% CI, 0.94-2.15; P=.09) and a toward lower risk in patients with two or more eye diseases (OR, 0.53; 95% CI, 0.24-1.15; P=.10). Medicaid insurance was the only significant (P=.02) independent risk factor of LTFU in the multivariate regression. CONCLUSION: We found a high rate of LTFU after anti-VEGF injections among patients with RVO, DR, AMD, and identified risk and protective factors associated with LTFU among this population. Although our results may not be generalizable, data on LTFU in a clinical practice setting are needed to understand the scope of the problem so that interventions may be designed to improve outcomes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22323号 / 医博第4564号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 横出 正之, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Age-related macular degeneration (AMD) is the leading cause for visual impairment in the elderly. The etiology of AMD remains unclear. Clinical and histopathological studies suggest that photoreceptors play a role in disease progression. Here, we found that photoreceptors of AMD patients show adaptive changes in gene expression, suggestive of a nutrient shortage. To study the effect of these changes, we mimicked the metabolic alteration in mouse photoreceptors, by disruption of the Tuberous Sclerosis Complex (TSC). This led to AMD hallmarks, including the advanced stages of geographic atrophy (GA) and choroidal neovascularization (CNV). Furthermore, we found that disease onset requires the activity of the mammalian target of rapamycin complex 1 (mTORC1). To study the contribution of photoreceptors to disease, we profiled retinal phospholipids as photoreceptors are rich in phospholipids. We found a reduction in two docosahexaenoic acid (DHA)-containing phospholipids. Feeding DHA to mutant mice, alleviated most AMD-associated hallmarks. To study the inflammatory complications seen with current anti-vascular endothelial growth factor (VEGF) treatments for CNV we used rAAV-mediated gene transfer to overexpress an anti-VEGF protein. We found that inhibition of VEGF can promote retinal inflammation. The data suggests that targeting photoreceptor metabolism may provide novel therapies to treat AMD.

Ackmann, Charlotte Osmotische Induktion des Komplementfaktors C9 in retinalen Pigmentepithelzellen Universität Leipzig, Dissertation 98 Seiten, 208 Literaturangaben, 28 Abbildungen, 8 Tabellen Die altersbedingte Makuladegeneration (AMD) ist die häufigste Ursache für Erblindung bei Erwachsenen in den industrialisierten Ländern. Die AMD ist unter anderem eine chronisch entzündliche Erkrankung, bei der die Aktivierung der alternativen Komplementkaskade eine Rolle spielt. Daneben erhöht Bluthochdruck, der auch durch eine salzreiche Ernährung getriggert wird, das Risiko an einer AMD zu erkranken. Untersucht wurde die Genexpression des Komplementfaktors C9 unter verschiedenen pathologischen Bedingungen in humanen retinalen Pigmentepithel (RPE)-Zellen sowie deren Wirkung auf die physiologischen Eigenschaften der Zellen. Gezeigt wird, dass die Expression des C9 Gens in humanen RPE-Zellen spezifisch durch Hyperosmolarität, Hypoxie und oxidativen Stress induziert wird. Die Menge an C9 Protein wurde durch Hyperosmolarität leicht aber signifikant erhöht. Die hyperosmotische Induktion der C9 mRNA ist abhängig von der Aktivierung der Signalproteine p38 MAPK, ERK1/2, JNK, PI3K, sowie der Transkriptionsfaktoren STAT3 und NFAT5 während für die Hypoxie-induzierte C9 mRNA Expression nur eine Beteiligung des Transkriptionsfaktors STAT3 nachgewiesen wurde. Die Aktivierung verschiedener Signalwege durch Hyper-osmolarität und Hypoxie lässt vermuten, dass eine hohe Kochsalzaufnahme auch unter normoxischen Verhältnissen die Eigenschaften RPE-Zellen verändert. Hyperosmolarität hemmt die Proliferation und Migration der RPE-Zellen, während chemische Hypoxie nur die Proliferationsrate verringert. Die Wirkung einer erhöhten extrazellulären NaCl-Konzentration auf die C9 mRNA Expression wird über zwei Mechanismen vermittelt: über die Erhöhung der extrazellulären Osmolarität und über die Veränderung des NaCl-Gradienten über der Plasmamembran. Die NaCl Wirkung über den veränderten NaCl-Gradienten lässt vermuten, dass eine übermäßige Aufnahme von Kochsalz nicht nur über die Erhöhung des Blutdruckes die Pathogenese der AMD stimuliert, sondern dass Kochsalz auch eine direkte stimulierende Wirkung auf RPE-Zellen besitzt. Diese Vermutung könnte erklären, weshalb hoher Blutdruck ein Risikofaktor der AMD ist, aber Medikamente zur Behandlung des Bluthochdruckes das Risiko der AMD nicht verändert.:Inhaltsverzeichnis Bibliographische Beschreibung IV Abkürzungsverzeichnis V 1. EINLEITUNG 1 1.1. Das retinale Pigmentepithel (RPE) 1 1.2. Die altersbedingte Makuladegeneration (AMD) 2 1.2.1. Die atrophe AMD 3 1.2.2. Die exsudative AMD 4 1.2.3. Die Aktivierung des Komplementsystems bei der exsudativen AMD 5 1.3. Risikofaktoren der AMD 7 1.4. Einfluss von Hypertonie auf die AMD 9 1.4.1. Hypertonie 9 1.4.2. Hypertonie als Risikofaktor der AMD 10 1.5. Therapie der AMD 11 2. FRAGESTELLUNG 13 3. MATERIAL UND METHODEN 14 3.1. Arbeitsmaterialien 14 3.1.1. Substanzen 14 3.1.2. Medien 15 3.1.3. Kits 15 3.1.4. Primer 16 3.1.5. Längenstandards 16 3.1.6. Antikörper 16 3.1.7. Rekombinante humane Proteine 17 3.1.8. Selektive Hemmer 17 3.1.9. Geräte 17 3.2. Zellbiologische Methoden 19 3.2.1. Zellkultivierung 19 3.2.2. Zellstimulation 20 3.2.3. Bestimmung der Proliferationsrate 21 3.2.4. Zellmigration 22 3.3. Molekularbiologische Methoden 23 3.3.1. RNA-Präparation 23 3.3.2. RNA Quantifizierung 24 3.3.3. cDNA-Synthese 24 3.3.4. Real-Time PCR 24 3.3.5. Agarose-Gel-Elektrophorese 26 3.3.6. Untersuchungen mit short interfering (si) RNA 27 3.4. Immunologische Methoden 28 3.4.1. Western Blot 28 3.4.1.1. Extraktherstellung aus RPE-Zellen 28 3.4.1.2. Proteinkonzentrationsbestimmung nach Bradford 29 3.4.1.3. SDS-Gelektrophorese 30 3.4.1.4. Western Blot 32 3.5. Statistische Auswertung 33 4. ERGEBNISSE 34 4.1. Regulation der Genexpression von Komplementfaktoren in RPE-Zellen 34 4.1.1. Hyperosmolarität erzeugt durch NaCl 34 4.1.2. Hyperosmolarität erzeugt durch Sucrose 36 4.1.3. Wirkung von Hypoosmolarität und oxidativem Stress 37 4.1.4. Wirkung von Hypoxie 38 4.1.5. Gemeinsame Wirkung von CoCl2 und NaCl 38 4.1.6. Wirkung von Zytokinen 39 4.1.7. Wirkung von Serum- und Gerinnungsfaktoren sowie Glukose 40 4.1.8. Wirkung von Entzündungsmediatoren 40 4.1.9. Wirkung von Matrixmetalloproteinase und Triamcinolon 41 4.2. Wirkung von Hyperosmolarität auf die Transkription und die Stabilität der C9 mRNA 42 4.3. Beteiligung intrazellulärer Signalwege und Transkriptionsfaktoren an der Induktion der C9 mRNA unter Hyperosmolarität und Hypoxie in RPE-Zellen 43 4.3.1. Beteiligung intrazellulärer Signalwege und Transkriptionsfaktoren an der NaCl-induzierten C9 mRNA Expression in RPE-Zellen 43 4.3.2. Hyperosmolare Induktion der C9 mRNA: Einfluss des Transkriptionsfaktors NFAT5 44 4.3.3. Beteiligung intrazellulärer Signalwege und Transkriptionsfaktoren an der Hypoxie-induzierten C9 mRNA Expression bei RPE-Zellen 46 4.4. Aktivierung intrazellulärer Signalproteine durch Hyperosmolarität bzw. Hypoxie 47 4.5. Wirkung von Hyperosmolarität auf das C9 Protein 48 4.6. Wirkung von Hyperosmolarität auf die physiologischen Eigenschaften der RPE- Zellen 50 4.6.1. Wirkung von Hyperosmolarität auf die Zellproliferation 50 4.6.2. Wirkung von Hyperosmolarität auf die Zellmigration 51 4.6.3. Wirkung von Hyperosmolarität auf die Zellvitalität 51 5. DISSKUSION 53 5.1. Wirkung von Hyper-, Hypoosmolarqität, Hypoxie und oxidativem Stress auf die Genexpression von C9 in humanen RPE-Zellen 53 5.3. Wirkung von Hyperosmolarität auf die Stabilität der C9 mRNA 56 5.4. Beteiligung intrazellulärer Signalwege und Transkriptionsfaktoren an der NaCl- bzw. CoCl2-induzierten C9 mRNA Expression in RPE-Zellen 56 5.5. Einfluss des Transkriptionsfaktors NFAT5 auf die hyperosmolare C9 Induktion 58 5.6. Aktivierung intrazellulärer Signalproteine durch Hyperosmolarität bzw. Hypoxie 58 5.7. Wirkung von Hyperosmolarität auf das C9 Protein 59 5.8. Wirkung des Komplementfaktors C9 und der Hyperosmolarität auf die physiologischen Eigenschaften von RPE-Zellen 60 5.8.1. Wirkung auf die Zellproliferation 60 5.8.2. Wirkung auf die Zellmigration 60 5.8.3. Wirkung auf die Zellvitalität 61 5.9. Bedeutung für das Verständnis der Pathogenese der AMD 61 6. ZUSAMMENFASSUNG 63 7. LITERATURVERSZEICHNIS 68 8. TABELLENVERZEICHNIS 85 9. ABBILDUNGSVERZEICHNIS 86 10. ANHANG 88 10.1. Eigenständigkeitserklärung 88 10.2. Lebenslauf 89 10.3. Danksagung 90

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20810号 / 医博第4310号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 清水 章, 教授 萩原 正敏, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21002号 / 医博第4348号 / 新制||医||1027(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 山田 亮, 教授 Shohab YOUSSEFIAN / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM