OBJECTIVE To determine whether grading for AMD during a diabetic retinopathy (DR) screening program would be cost-effective in Hong Kong. METHODS A cost-effectiveness analysis based on a Markov model with six mutually exclusive health states was undertaken. It included grading for AMD and treatment with vitamin therapy for those with intermediate AMD. The outcome of the model was cost per quality-adjusted life year (QALY) gained. A public provider perspective was used. The measures of effectiveness were mostly taken from a local DR screening project except the transition probabilities and the utility values which were taken from overseas data. Costs were mainly taken from the Hospital Authority and salary scale 2009. The main assumptions and estimates were tested in sensitivity analyses. In this model, only subjects with non-sight threatening diabetic retinopathy were included and the possibility of disease regression and treatment benefit for those with advanced AMD were not considered. Both costs and benefits were discounted at 3%. RESULTS The cost per QALY gained through grading for AMD at the time of DR screening and treatment with vitamins of appropriate cases was HK$47,397 after discounting. This would be considered highly cost-effective based on the World Health Organization’s threshold of willingness-to-pay (WTP) for a QALY, e.g. less than the annual per capita GDP HK$300,000. One way sensitivity analyses revealed that the cost per QALY was most sensitive to utility value, discount rate, progression rate from intermediate to advanced AMD, and compliance rate for the treatment. The cost-effectiveness acceptability curve showed that at a WTP for a QALY of $100,000 or more, this AMD screening programme has over 90% of probability of being cost-effective compared with no screening. CONCLUSION Our cost-effectiveness analysis demonstrated that grading for AMD at the time of DR screening among diabetic patients would probably be cost-effective in a Hong Kong public hospital setting. / published_or_final_version / Public Health / Master / Master of Public Health

No description available.

Age-related macular degeneration (AMD) causes vision impairment which is not recoverable under existing treatment options. It has been a major leading cause of blindness in the aged population. To ameliorate the self-care ability for AMD patients, educational interventions to mediate negative impacts of the disease on quality of life have become a research interest. Current practice in the proposed Hong Kong setting, Elderly Health Centre A and Elderly Health Centre B, depends on nurses giving general advice which is lack of scientific support and non-specific to AMD. Purpose of this dissertation is to translate the best evidence to practice for improving the care of older adults with AMD in the proposed setting. Evidences showed that self-management education programmes were effective in improving emotional distress and self-efficacy. Electronic searches located 9 relevant RCTs of high level and methodologically strong evidences. Data was extracted into tables of evidence. Data summary and synthesis was presented. Assessment on the implementation potential indicated that the SEP was worth to try in the local setting. Twelve recommendations for the practice guidelines of SEP were presented and a communication process to facilitate the change in a top-down approach was introduced. A pilot study plan in Centre A followed by a main study in Centre A and Centre B was presented. A total of 98 elderly patients with AMD will be recruited as 10 SEP groups. Approximately 1.8 years will be used to finish the main study. Outcomes will be measured at the 6th week follow-up. ‘Emotional distress’ will be measured as primary outcome and ‘self-efficacy’ will be measured as secondary outcome. ‘Client satisfaction’, ‘staff satisfaction’ and the ‘utilization rate of the innovation’ will also be assessed in evaluation. A two-tailed paired (one-sample) t-test will be adopted for analysis, with a 95% confidence interval. The basis for effectiveness for the outcome measurements and basis for adoption of the clinical guidelines were stated. Adoption of the developed guidelines in the local setting will optimistically improve the substantial clinical outcomes for AMD patients, mediating the negative impacts of vision impairment or vision loss on their quality of life. / published_or_final_version / Nursing Studies / Master / Master of Nursing

年齡相關性黃斑變性（AMD）是發展國家高齡人群中不可逆盲的首要原因。在AMD患者中，即使在改變生活模式或進行治療后，其滲出性亞型仍導致超過80% 的病例出現嚴重視力喪失及法定盲。息肉狀脈絡膜血管病變 （PCV）是一種與滲出性AMD在臨床表型上存在相同之處的黃斑病變，它的典型病變被定性為眼底血管螢光造影時出現息肉狀的病灶。近年PCV被認為是滲出性AMD亞型中的一種，因為兩者共享相同的基因成份及環境因素。然而，PCV曾經被認為是與滲出性AMD截然不同的一種疾病，由於兩者的臨床表現並不一致。另外，PCV病人相對年輕，多為亞洲人，以及對光動力治療和抗血管內皮生長因子治療存在不同的反應。一個明確的鑒別診斷可以更好的輔助臨床醫生對患有這些疾病的老年病人進行管理，然而兩者是相同還是不同的疾病種類仍是一個具爭議性的議題。 / CFH 基因和ARMS2/HTRA1位點已被全基因組相關性研究及相關的分子學研究定位為AMD候選基因。鑒於FPR1基因的協調吞噬性白細胞激活及遷移的功能，它可能是一個新的AMD候選基因。本論文評估在滲出性AMD和PCV中FPR1作為一個新的疾病基因基因的可能，獲取滲出性AMD和PCV病人中的CFH，ARMS2，HTRA1和FPR1基因檔案，同時研究在ARMS2/HTRA1位點中基因型和疾病表型的關聯性，以此從基因學方面鑑別滲出性AMD與PCV。 / 本研究在滲出性AMD，PCV病例和對照人群中使用聚合酶鏈反應和直接測序法進行ARMS2， HTRA1， CFH 和FPR1基因篩查。本研究發現滲出性AMD和PCV之間存在不同的基因型分佈，關聯模式以及基因效應值。 / 在HTRA1的多態性中，rs11200638，rs2672598, rs1049331 和 rs2293870 在滲出性AMD和PCV之間表現出鑒別性關聯 （p < 0.001）。其中rs11200638 (p = 1.48×10⁻⁴) and rs2672598 (p = 2.27×10⁻³) 在滲出性AMD病人中相互校正后仍保持各自的顯著性，但rs2672598 未能在PCV病人中保持顯著性(p = 0.20)。並且本研究發現攜帶rs11200638和 rs2672598聯合基因型AA-CC 的病人更傾向是滲出性AMD病人，與PCV相比幾率高11.7倍。 / 在ARMS2中，有11個基因多態性與滲出性AMD和PCV存在顯著性的相關。在與rs11200638校正后，rs10490924保持和滲出性AMD的顯著相關性(p = 0.011)，但PCV中未能保持(p = 0.077)。同時，元分析結果顯示ARMS2 rs10490924和HTRA1 rs11200638不同人群的PCV中的等位基因相關性是一致的。 / 在FPR1中，rs78488639與滲出性AMD (p = 0.049, 比值比 (OR) = 2.05, 95% 信賴區間（CI）: 1.014.14)和PCV (p = 0.016, OR = 2.27, 95%CI: 1.154.47)的疾病風險存在顯著的相關性。多態性rs104229的G等位基因純合子和滲出性AMD存在顯著相關(p = 0.039, OR = 2.27, 95%CI: 1.084.74)，但在PCV中未發現相關性(p = 0.24)。多態性rs2070746 AMD (p = 0.021, OR = 0.57, 95%CI: 0.35 0.91)和rs867229 (p = 0.0091, OR = 0.54, 95%CI: 0.340.86) 的雜合子基因型與滲出性AMD相關，但在PCV中未發現相關性。與此同時，本研究在上述多態性中發現滲出性AMD和PCV之間不同的基因型分佈。 / 本研究發現在滲出性AMD和PCV病人中FPR1 rs78488639和CFH rs800292存在顯著的相互作用（ORs > 4）。兩個多態性之間的相互作用提高滲出性AMD和PCV的疾病風險，而不是僅對其中之一起作用。 / ARMS2 多態性 rs10490924 (A69S, 205G>T, pAMD = 1.01×10⁻²⁹ OR = 7.91, 95% CI: 4.93 - 12.67; pPCV = 8.25×10⁻⁷, OR = 3.51, 95% CI: 1.98 - 5.03), HTRA1 多態性rs11200638 (-625G>A, pAMD = 9.88×10⁻²⁸, OR = 6.95, 95% CI: 4.37 - 11.06; pPCV = 8.02×10⁻⁶, OR = 2.82, 95%CI: 1.77 - 4.47), CFH 多態性rs800292 (V62I, 184G>A, pAMD = 9.00×10⁻⁴ , OR = 0.58, 95% CI: 0.42 0.79; pPCV = 0.011, OR = 0.66, 95% CI: 0.49 0.90) and FPR1 多態性rs78488639 (L97M, 289C>A, pAMD = 0.049, OR = 2.05, 95% CI: 1.01 - 4.14; pPCV = 0.016, OR = 2.27, 95% CI: 1.15 - 4.47)代表各自基因的最強相關性。此外，元分析揭示了在不同種族人群PCV中的等位基因相關性顯著並且一致(ORtotal = 2.14, 95% CI: 1.97 2.33, ORtotal = 2.34, 95% CI: 1.98 2.76 and ORtotal = 0.49, 95% CI: 0.44 0.56)。表型-基因型分析發現ARMS2/HTRA1 的風險基因型和較差的治療反應呈正相關性(p = 0.04)。另外，本研究在滲出性AMD中發現HTRA1 rs11200638和吸煙的聯合作用。然而，在PCV中未觀察到次聯合作用，這可能提示兩者間存在不同的疾病機制。 / 本論文提出FPR1基因是一個新的滲出性AMD和PCV候選基因，揭示了ARMS2，HTRA1，CFH和FPR1在滲出性AMD和PCV間顯著並且一致的相關性， 提供鑒別兩者的基因學證據，闡明了ARMS2/HTRA1 的風險基因型和較差的治療反應之間的相關性以及顯示了吸煙在滲出性AMD和PCV之間的不同影響。然而，由於兩者間基因關聯的趨勢一致，目前尚未能清晰界定兩者的不同。因此，要進一步明確鑒別滲出性AMD和PCV，還需要進行不同種族的複製研究，以及更重要的是，尋找特定的PCV基因以鑒別兩個不同疾病。 / Age-related macular degeneration (AMD) is the leading cause of irreversible blindness for the elderly in developed countries. Its exudative subtype accounts for more than 80% of severe visual loss or legal blindness in AMD patients regardless of modified lifestyle and therapeutic treatments. Polypoidal choroidal vasculopathy (PCV) is a macular disorder characterized by typical polypoidal lesions on fundus angiograhpy and sharing similar phenotype with exudative AMD. PCV was suggested as a distinct disease from exudative AMD based on different clinical features in ophthalmic imaging. Furthermore, PCV patients tend to be younger and more prevalent in Asian, and have different responses to photo-dynamic therapy and anti-vascular endothelial growth factor treatments, compared to exudative AMD patients. Howerver, it has also been suggested that PCV could be a subtype of exudative AMD mainly because of their common genetic and environmental factors. Therefore, genetic differentiation between exudtive AMD and PCV might assist clinicans to determine the condition. / The complement factor H (CFH) gene, and age-related maculopathy susceptibility 2 (ARMS2)/high temperature requirement factor A1 (HTRA1) locus have been mapped for AMD by genome-wide association studies (GWAS) and subsequent molecular investigations. The formyl peptide receptor 1 (FPR1) gene, which mediates trafficking and activation of phagocytic leukocytes, is related to the AMD-associated inflammatory condition. This thesis aims to evaluate FPR1 as a novel disease gene for exudative AMD and PCV, to compare the genetic profiles of ARMS2, HTRA1, CFH, and FPR1 in exudative AMD and PCV, to investigate the correlation of ARMS2/HTRA1 genotypes with disease phenotypes, and to differentiate these two disorders throught the genomic compositions. / Case-control association studies were conducted on ARMS2, HTRA1, CFH and FPR1 in exudative AMD and PCV patients of our Hong Kong Chinese cohort using polymerase chain reaction and direct sequencing. We observed different genotypic distributions (p < 0.05), association patterns and effect sizes between these two diseases. / In HTRA1 polymorphisms, rs11200638, rs2672598, rs1049331 and rs2293870 showed differential associations between exudative AMD and PCV (p < 0.001). Both rs11200638 (p = 1.48×10⁻⁴) and rs2672598 (p = 2.27×10⁻³) remained significant after adjusting for each other in exudative AMD, whereas rs2672598 was not significantly associated with PCV (p = 0.20). The joint genotype AA-CC constructed by the risk alleles of these rs11200638 and rs2672598 were prone to exudative AMD, conferring an 11.7-fold higher risk (p = 4.00×10⁻³) when compared to PCV. / In ARMS2, 11 single nucleotide polymorphisms (SNPs) showed significant associations with both exudative AMD and PCV. After adjusting for rs11200638, ARMS2 rs10490924 remained significantly associated with exudative AMD (p = 0.011), but not with PCV (p = 0.077). / In FPR1, SNP rs78488639 significantly increased the risk to exudative AMD (p = 0.049, odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.014.14) and PCV (p = 0.016, OR = 2.27, 95%CI: 1.154.47). The homozygous G allele of rs1042229 was associated with exudative AMD (p = 0.039, OR = 2.27, 95%CI: 1.084.74), but not with PCV (p = 0.24). The heterozygous genotypes of rs2070746 and rs867229 were associated with exudative AMD (p = 0.021, OR = 0.57, 95%CI: 0.35 0.91; p = 0.0091, OR = 0.54, 95%CI: 0.340.86, respectively), but not with PCV. / Significant interaction was identified between FPR1 rs78488639 and CFH rs800292, with joint ORs > 4 folds for both exudative AMD and PCV. Interactions between FPR1 rs78488639 with CFH rs800292 enhance risks to both AMD and PCV, not just one of them. / Overall, the ARMS2 rs10490924 (A69S, 205G>T, pAMD = 1.01×10⁻²⁹, OR = 7.91, 95% CI: 4.93 - 12.67; pPCV = 8.25×10⁻⁷, OR = 3.51, 95% CI: 1.98 - 5.03), HTRA1 rs11200638 (-625G>A, pAMD = 9.88×10⁻²⁸, OR = 6.95, 95% CI: 4.37 - 11.06; pPCV = 8.02×10⁻⁶, OR = 2.82, 95%CI: 1.77 - 4.47), CFH rs800292 (V62I, 184G>A, pAMD = 9.00×10⁻⁴ , OR = 0.58, 95% CI: 0.42 0.79; pPCV = 0.011, OR = 0.66, 95% CI: 0.49 0.90) and FPR1 rs78488639 (L97M, 289C>A, pAMD = 0.0487, OR = 2.05, 95% CI: 1.01 - 4.14; pPCV = 0.0161, OR = 2.27, 95% CI: 1.15 - 4.47) were responsible for the strongest association in each gene. Moreover, meta-analysis revealed a consistent and significant association of the ARMS2/HTRA1 locus with PCV in different ethnic cohorts (OR{U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 2.14, 95% CI: 1.97 2.33, OR{U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 2.34, 95% CI: 1.98 2.76 and {U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 0.49, 95% CI: 0.44 0.56, respectively). The phenotype-genotype analysis implicated a positive correlation between ARMS2/HTRA1 risk genotype and a worse response to treatment (p = 0.04) in our exudative AMD patients. In addition, joint effects between cigarette smoking and HTRA1 rs11200638 was found in exudative AMD group. However, this effect was not significant in PCV group, which might implicate a different disease mechanism. / This thesis attempts to dissect the genetic profiles of exudative AMD and PCV. Results in this thesis suggest FPR1 as a novel candidate gene for exudative AMD and PCV, reveal a significant and consistent association of ARMS2, HTRA1, CFH and FPR1 with both exudative AMD and PCV, provide evidences for genetic differentiation of these two disorders, demonstrate a significant correlation between ARMS2/HTRA1 genotypes and response to treatment, and indicate different influence of smoking in exudative AMD and PCV. However, definite differentiation between exudative AMD and PCV was limited because of the same trend of associations between these two disorders. Therefore, replication studies in other enthic populations are necessary, and identification of PCV-specific genes/polymorphisms could further differentiate PCV from exudative AMD. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liang, Xiaoying. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 124-143). / Abstract also in Chinese. / Title page --- p.i / Abstract --- p.iii / 摘要 --- p.vii / Acknowledgements --- p.xii / Table of Contents --- p.xiii / List of Figures --- p.xix / List of Tables --- p.xxi / Abbreviations --- p.xxiv / Publications --- p.xxvii / Conference Presentations --- p.xxviii / Chapter Chapter 1: --- Introduction / Chapter 1.1. --- Normal retinal architecture --- p.1 / Chapter 1.2. --- Age-related retinal changes --- p.3 / Chapter 1.3. --- Age-related macular degeneration (AMD) --- p.7 / Chapter 1.3.1. --- Classification, clinical manifestation and disease course --- p.7 / Chapter 1.3.2. --- Exudative AMD and therapeutic strategies --- p.9 / Chapter 1.3.3. --- Pathology of AMD --- p.10 / Chapter 1.3.4. --- Risk factors and associated pathogenesis --- p.12 / Chapter 1.3.4.1. --- Age --- p.12 / Chapter 1.3.4.2. --- Ethnicity --- p.13 / Chapter 1.3.4.3. --- Oxidative stress --- p.13 / Chapter 1.3.4.3.1. --- Reactive oxygen species and AMD --- p.14 / Chapter 1.3.4.3.2. --- Antioxidants --- p.15 / Chapter 1.3.4.3.3. --- Association of oxidation genes with AMD --- p.16 / Chapter 1.3.4.4. --- Inflammation --- p.16 / Chapter 1.3.4.4.1. --- Complement in AMD --- p.17 / Chapter 1.3.4.4.2. --- The potential role of formyl peptide receptor 1 (FPR1) in AMD --- p.19 / Chapter 1.3.4.5. --- Genetic predisposition --- p.19 / Chapter 1.3.4.5.1. --- Complement factor H --- p.21 / Chapter 1.3.4.5.2. --- The 10q26 locus --- p.22 / Chapter 1.3.4.5.3. --- Phenotype-genotype correlation --- p.23 / Chapter 1.4. --- Comparisons between exudative AMD and Polypoidal choroidal vasculopathy --- p.24 / Chapter 1.4.1. --- History --- p.25 / Chapter 1.4.2. --- Natural course --- p.26 / Chapter 1.4.3. --- Epidemiological factors --- p.27 / Chapter 1.4.3.1. --- Ethnicity --- p.27 / Chapter 1.4.3.2. --- Gender --- p.27 / Chapter 1.4.3.3. --- Age --- p.28 / Chapter 1.4.3.4. --- Risk factors --- p.28 / Chapter 1.4.4. --- Clinical manifestation and histopathological features --- p.29 / Chapter 1.4.5. --- Genetic determinants --- p.29 / Chapter 1.4.5.1. --- Genes with common associations --- p.30 / Chapter 1.4.5.2. --- Genes not have common association --- p.32 / Chapter 1.4.6. --- Response to treatments --- p.32 / Chapter 1.5. --- Objectives and research prospects --- p.33 / Chapter Chapter 2: --- Materials and Methods / Chapter 2.1. --- Polymorphism identification in ARMS2, HTRA1, FPR1 and CFH --- p.39 / Chapter 2.1.1. --- Study subjects --- p.39 / Chapter 2.1.1.1. --- Diagnostic features of AMD and PCV --- p.39 / Chapter 2.1.1.2. --- Control subjects --- p.40 / Chapter 2.1.2. --- Laboratory methods --- p.40 / Chapter 2.1.2.1. --- DNA extraction and quantification --- p.40 / Chapter 2.1.2.2. --- Genotyping --- p.41 / Chapter 2.1.2.2.1. --- Polymerase chain reaction (PCR) and agrose gel electrophoresis --- p.41 / Chapter 2.1.2.2.2. --- DNA sequencing --- p.42 / Chapter 2.1.3. --- Statistical analysis --- p.43 / Chapter 2.1.3.1. --- Genotypic association analysis --- p.43 / Chapter 2.1.3.2. --- Haplotype association analysis --- p.43 / Chapter 2.1.3.3. --- Logistic regression analysis --- p.44 / Chapter 2.1.3.4. --- Joint effect analysis --- p.44 / Chapter 2.1.3.5. --- Meta-analysis --- p.45 / Chapter 2.1.3.6. --- Statistical power calculation and sample size --- p.45 / Chapter 2.2. --- Phenotype-genotype correlation in ARMS2/HTRA1 locus --- p.46 / Chapter 2.2.1. --- Patient recruitment --- p.46 / Chapter 2.2.2. --- Genotyping --- p.46 / Chapter 2.2.3. --- Outcome measurement --- p.46 / Chapter 2.2.4. --- Statistical analysis --- p.47 / Chapter Chapter 3: --- Results / Chapter 3.1. --- The age and gender distribution in study subjects --- p.57 / Chapter 3.2. --- The HTRA1 sequencing in exudative AMD and PCV --- p.57 / Chapter 3.2.1. --- Polymorphism identification and genotypic association --- p.57 / Chapter 3.2.2. --- Haplotype structure and Haplotype-based association analysis --- p.59 / Chapter 3.2.3. --- Joint genotype analysis --- p.59 / Chapter 3.3. --- Differential association of exudative AMD and PCV with the ARMS2/HTRA1 locus --- p.60 / Chapter 3.3.1. --- Genotypic association --- p.60 / Chapter 3.3.2. --- Haplotype analysis --- p.62 / Chapter 3.3.3. --- Logistic regression --- p.63 / Chapter 3.3.4. --- Meta-analysis of ARMS2/HTRA1 association with PCV --- p.64 / Chapter 3.3.5. --- In-position OR plot --- p.64 / Chapter 3.4. --- FPR1 and CFH in exudative AMD and PCV --- p.65 / Chapter 3.4.1. --- Polymorphism identification and genotypic association --- p.65 / Chapter 3.4.2. --- Haplotype analysis of FPR1 --- p.66 / Chapter 3.4.3. --- The association of CFH rs800292 --- p.67 / Chapter 3.4.4. --- Joint effect analysis of the CFH and FPR1 genes --- p.67 / Chapter 3.4. --- Phenotype-genotype correlation in ARMS2/HTRA1 locus --- p.68 / Chapter 3.4.1. --- Distribution of age and bilaterality --- p.69 / Chapter 3.4.2. --- Greatest linear dimension of CNV lesion in exudative AMD --- p.69 / Chapter 3.4.3. --- Response to treatment in exudative AMD --- p.69 / Chapter 3.4.4. --- Recurrence in PCV --- p.70 / Chapter 3.4.5. --- Smoking status --- p.70 / Chapter Chapter 4: --- Discussion / Chapter 4.1. --- Age and gender distribution --- p.104 / Chapter 4.2. --- Genetic differentiation in ARMS2/HTRA1 locus --- p.S104 / Chapter 4.2.1. --- SNPs with common association --- p.106 / Chapter 4.2.2. --- SNPs with different association S --- p.106 / Chapter 4.2.3. --- Comparison with previous studies C --- p.107 / Chapter 4.2.4. --- Sample size S --- p.109 / Chapter 4.3. --- The FPR1 gene in exudative AMD and PCV --- p.110 / Chapter 4.4. --- Interaction between FPR1 and CFH --- p.112 / Chapter 4.5. --- Correlation between phenotypes and genotypes --- p.113 / Chapter 4.6. --- Common and rare variants for complex disease --- p.114 / Chapter 4.6.1. --- The debate of common disease common variant versus common disease rare variant --- p.115 / Chapter 4.6.2. --- Candidate gene screening versus geno-wide association study --- p.117 / Chapter 4.6.3. --- Common variants versus rare variants in 10q26 locus --- p.118 / Chapter 4.6.3.1. --- Common variants --- p.119 / Chapter 4.6.3.2. --- Rare variants --- p.120 / Chapter Chapter 5: --- Conclusions and future prospects --- p.122 / Chapter Chapter 6: --- References --- p.124

This research investigated the influence of the normal aging process on truly photopic achromatic and chromatic retinal increment threshold over an extensive range of colored targets. It was found that for both achromatic and chromatic retinal thresholds there is a significant correlation between advancing age and the stimulus luminance intensity at threshold across the visible spectrum. This correlation is greater for the short wavelength range than for both the middle and the long wavelength ranges (r² (achromatic)= 0.43; r²(chromatic) = 0.49. In addition, a small exploratory study was completed which examined the role of prereceptoral changes in these age-related differences in color vision function. Results from this preliminary study (Experiment II) support the supposition that prereceptoral factors cannot account for all of the age-related losses that are seen in visual function, particularly in the middle and long wavelength ranges of the visible spectrum. / Arts, Faculty of / Psychology, Department of / Graduate

Indiana University-Purdue University Indianapolis (IUPUI) / Choroidal neovascularization (CNV) is the vision-threatening characteristic of wet age-related macular degeneration (AMD), a major cause of blindness affecting almost 2 million elderly Americans. The current approved treatments target the dominant angiogenic mediator, vascular endothelial growth factor (VEGF). However, repeated injections of anti-VEGF drugs can cause ocular and systemic side effects, and about 30% of wet AMD patients are non-responsive. There is thus an unmet need to develop VEGF-independent antiangiogenic molecules to complement or combine with existing medications. I studied SH-11037, a novel homoisoflavonoid with potent and selective antiangiogenic activity against human retinal endothelial cells. Intravitreal SH- 11037 dose-dependently suppressed angiogenesis in the laser-induced CNV (LCNV) mouse model. These effects were prominent as early as 7 days post-laser treatment as measured by a novel ellipsoid quantification method of optical coherence tomography images in vivo. A supratherapeutic dose of 100 μM SH- 11037 was not associated with signs of murine ocular toxicity, and did not interfere with pre-existing retinal vasculature or retinal function. SH-11037 synergized with anti-VEGF therapy in vitro and in vivo, suggesting a VEGFindependent mechanism. By photoaffinity pulldown, I identified soluble epoxide hydrolase (sEH) as an SH-11037-binding target. sEH is a key enzyme in ω-3 and ω-6 fatty acid metabolism. sEH levels were dramatically upregulated in retinal sections from L-CNV mice and a specific sEH inhibitor, t-AUCB, significantly suppressed L-CNV lesion volume. Additionally, SH-11037 inhibited sEH enzymatic activity in vitro and in vivo in L-CNV mice. Given the role of sEH in the metabolism of docosahexaenoic acids (DHA), inhibition of sEH using small molecules like SH-11037 would enhance ocular DHA levels, with beneficial antiangiogenic and anti-inflammatory effects. SH-11037 is thus a novel sEH inhibitor, which could make it an alternative or additive therapy to existing anti- VEGF drugs for treatment of neovascular diseases in the eye and other tissues.

Indiana University-Purdue University Indianapolis (IUPUI) / Prevention of pathological angiogenesis is a key strategy for treatment of common blinding ocular diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The current treatment strategies are associated with partial vision loss and are ineffective in a significant patient population. Hence novel drugs as well as new ways to target ocular angiogenesis are needed for treating these diseases. I pursued a natural antiangiogenic compound, cremastranone, to develop novel drug leads and to find new targets. The objective of my doctoral thesis project was to elucidate cremastranone’s molecular mechanism of action and optimize its structureactivity relationship (SAR). In order to achieve this goal, with the help of chemistry collaborators cremastranone was synthesized for the first time. I showed that cremastranone has 50-fold more potency against endothelial cells as compared to nonendothelial cells, and also tested a novel active isomer, SH-11052. By SAR studies I identified a potent molecule, SH-11037, that has 10-fold more selectivity against retinal endothelial cells as compared to macrovascular endothelial cells. I then elucidated cremastranone’s molecular mechanism using a chemical proteomic approach. I identified ferrochelatase (FECH) as a specific interacting protein partner of cremastranone using photoaffinity chromatography. Hence, I hypothesized that cremastranone exerts its antiangiogenic activities through modulation of the functions of FECH. Cremastranone inhibited the enzymatic activity FECH in endothelial cells. Therefore, I investigated the role of FECH in ocular angiogenesis. Partial loss of FECH, using a siRNA-based knock down approach, decreased retinal angiogenesis both in vitro and in vivo in mouse models. Knock down of FECH decreased the expression levels of key proangiogenic proteins HIF-1α, eNOS, and VEGFR2. This work suggests that ferrochelatase plays an important, previously undocumented role in angiogenesis and that targeting of this enzyme by cremastranone might be exploited to inhibit pathological angiogenesis in ocular diseases.