{"id":{"repo_id":"iupui","oai_identifier":"oai:scholarworks.indianapolis.iu.edu:1805/10604"},"canonical_url":"https://search.dev.ndltd.org/etd/iupui/oai:scholarworks.indianapolis.iu.edu:1805/10604","repository":{"repo_id":"iupui","name":"IUPUI","base_url":"https://scholarworks.indianapolis.iu.edu/server/oai/request"},"display":{"title":"Mechanistic and therapeutic evaluation of a novel antiantiogenic small molecule","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Sulaiman, Rania S."],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Corson, Timothy W."],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-05-24","date_published":"2016-05-24","updated_at":"2026-07-24T02:42:13Z","subjects":["Ocular Angiogenesis","Small molecule","Wet age-related macular degeneration","Choroidal neovascularization"],"languages":["en_US"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.7912/C29W2Z"],"render_values":[{"text":"10.7912/C29W2Z","href":"https://doi.org/10.7912/C29W2Z","code":true}]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://dx.doi.org/10.7912/C2/316"],"render_values":[{"text":"http://dx.doi.org/10.7912/C2/316","href":"http://dx.doi.org/10.7912/C2/316","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1805/10604","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Corson, Timothy W."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Cummins, Theodore R.","Jerde, Travis J.","Lu, Tao","Boulton, Michael E."]},{"key":"dc:creator","label":"Author","values":["Sulaiman, Rania S."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2016-08-08T17:40:10Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2016-08-08T17:40:10Z"]},{"key":"dc:date.issued","label":"Date","values":["2016-05-24"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Ocular Angiogenesis","Small molecule","Wet age-related macular degeneration","Choroidal neovascularization"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.7912/C29W2Z"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1805/10604","http://dx.doi.org/10.7912/C2/316"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Indiana University-Purdue University Indianapolis (IUPUI)"]},{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:title","label":"Title","values":["Mechanistic and therapeutic evaluation of a novel antiantiogenic small molecule"]}]}],"canonical_facts":{"dc:contributor.advisor":["Corson, Timothy W."],"dc:contributor.other":["Cummins, Theodore R.","Jerde, Travis J.","Lu, Tao","Boulton, Michael E."],"dc:creator":["Sulaiman, Rania S."],"dc:date.accessioned":["2016-08-08T17:40:10Z"],"dc:date.available":["2016-08-08T17:40:10Z"],"dc:date.issued":["2016-05-24"],"dc:description":["Indiana University-Purdue University Indianapolis (IUPUI)"],"dc:description.abstract":["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."],"dc:identifier.doi":["10.7912/C29W2Z"],"dc:identifier.uri":["https://hdl.handle.net/1805/10604","http://dx.doi.org/10.7912/C2/316"],"dc:language.iso":["en_US"],"dc:subject":["Ocular Angiogenesis","Small molecule","Wet age-related macular degeneration","Choroidal neovascularization"],"dc:title":["Mechanistic and therapeutic evaluation of a novel antiantiogenic small molecule"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T02:42:13Z"}