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.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10690 |
| Date | 16 May 2016 |
| Creators | Basavarajappa, Halesha Dhurvigere |
| Contributors | Corson, Timothy W., Grant, Maria B., Hurley, Thomas D., Quilliam, Lawrence A., Chan, Rebecca |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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