Ferrochelatase is a therapeutic target for ocular neovascularization

Ocular neovascularization underlies major blinding eye diseases such as “wet” age-related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo. FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function in the Fechm1Pas mouse model reduces choroidal neovascularization. FECH depletion modulates endothelial nitric oxide synthase function and VEGF receptor 2 levels. FECH is inhibited by the oral antifungal drug griseofulvin, and this compound ameliorates choroidal neovascularization in mice when delivered intravitreally or orally. Thus, FECH inhibition could be used therapeutically to block ocular neovascularization

The impact of ancillary services in optimal DER investment decisions

Microgrid resource sizing problems typically include the analysis of a combination of value streams such as peak shaving, load shifting, or load scheduling, which support the economic feasibility of the microgrid deployment. However, microgrid benefits can go beyond these, and the ability to provide ancillary grid services such as frequency regulation or spinning and non-spinning reserves is well known, despite typically not being considered in resource sizing problems. This paper proposes the expansion of the Distributed Energy Resources Customer Adoption Model (DER-CAM), a state-of-the-art microgrid resource sizing model, to include revenue streams resulting from the participation in ancillary service markets. Results suggest that participation in such markets may not only influence the optimum resource sizing, but also the operational dispatch, with results being strongly influenced by the exact market requirements and clearing prices

Examining LRP4’s Capacity to Participate in Inhibitory WNT Signaling in Bone Cells

Context: In states of health, bone mass is sustained in a coordinated effort by osteoblasts, osteoclasts, and osteocytes. WNT signaling through low-density lipoprotein receptor related protein 5/6 (LRP5/LRP6) is one of the central signaling pathways that aids in controlling bone homeostasis. A prominent antagonist of the WNT signaling pathway is sclerostin. Low-density lipoprotein receptor related protein 4 (LRP4) is required to facilitate sclerostin-mediated inhibition of LRP5/LRP6. Clinically, mutations in LRP4 (R1170W and W1186S) which diminish its ability to bind sclerostin result in bone overgrowth. The mechanism by which LRP4 participates in this process is unknown. In vitro experiments suggest that LRP4 physically binds sclerostin and presents it directly to nearby LRP5/LRP6. Objective: Delineating the mechanistic function(s) of LRP4 is important because if LRP4 directly provides sclerostin to LRP5/LRP6 then interfering with this process represents a potential therapeutic intervention for promoting anabolic bone formation. Design: Genetic cloning is currently underway to fluorescently tag LPR5, LRP6, LRP4 and the LRP4 missense mutation (R1170W) for FRET/FLIM microscopy experiments. FRET/FLIM microscopy will be used to examine the live in vitro signaling dynamics of LRP4. Results: We expect to determine if LRP4 co-localizes with LRP5 or LRP6 in living bone cells, whether this co-localization is sclerostin dependent, and whether the LRP4 missense mutation affects this interaction. Our results will characterize the novel role LRP4 plays in sclerostin-mediated WNT inhibition and capacity to effect bone mass