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Vascular Biology

The vasculature connects every organ system in our bodies and represents the largest barrier separating organ environments and the systemic circulation. We are interested in peptides that regulate angiogenesis and the maintenance of a healthy vasculature. ELABELA is a 32 aa peptide from the SEP mini-proteome that we discovered to be an endogenous peptide ligand for the G-protein coupled receptor APLNR. ELABELA is required for embryonic (Chng, Ho..Reversade, Dev Cell, 2013) and placental angiogenesis (Ho..Reversade, Science, 2017). Dysregulated ELABELA expression has also be been linked to hypertensive disorders such as pre-eclampsia (Ho..Reversade, Science, 2017) and pulmonary hypertension (Yang..Davenport, Circulation, 2017). We are currently investigating the mechanisms of ELA downstream of APLNR in regulating angiogenic sprouting in both normal and pathological states, using the mouse retina as a model.

 

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ELABELA : a circulating peptide hormone

(from Ho et al., Science, 2017)

Expression of ELABELA in the mouse retinal vasculature

Chronic inflammation of the vasculature has been widely implicated as the trigger for cardiovascular disorders such as coronary and peripheral artery disorders. We are currently working to delineate pathways that mediate and potentiate chronic vascular inflammation, focusing on novel SEP discovery that can provide targets for intervention.

 

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Mitochondria

The mitochondrion is a multifunctional organelle that co-ordinates energy levels, metabolites and reactive oxygen species to maintain cellular homeostasis or induce apoptosis. We recently made the observation that mitochondria are a hotspot for SEP function (Zhang..Ho, 2020, BioRxiv). Along with others in the field, we have discovered a compendium of nuclear-encoded mitochondria-localized SEPs, which we term as mito-SEPs. These peptides engage in a wide variety of functions such as electron transport, fatty acid oxidation, protein quality control to name a few. We are actively investigating the mechanisms of select mito-SEPs, deciphering their individual contribution to oxidative metabolism and cardio-metabolic health. For instance, we discovered that BRAWNIN, a 71aa peptide that resides in the inner mitochondrial membrane is crucial for the assembly of Complex III or cytochrome bc oxidase. Deletion of Brawnin in zebrafish results in failure-to-thrive syndrome characterized by lactic acidosis, growth retardation and mitochondrial deficiency.

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Mito-SEPs of unknown function (MSUFs) discovered by our platform (from Zhang, 2020, BioRxiv)

Deletion of mito-SEP Brawnin results in growth retardation secondary to mitochondrial failure