Exploiting Tie2 Activation for the Treatment of Vascular Diseases

Project: Research project

Description

Loss of the quiescent endothelial phenotype is central to the pathogenesis and
progression of a broad spectrum of severe diseases including diabetic complications,
sepsis and cardiovascular disease. The current dearth of therapies available to treat
vascular dysfunction in these diseases underscores the need to develop new
approaches for treatment. We suggest that the Angiopoietin-Tie2/Tek vascular signaling
pathway is a promising new target. For example, delivery of Angiopoietin1, prevents
vascular leak and inflammation, while promoting endothelial survival in both cell culture
and transgenic models. In patients with critical vascular diseases, alterations in
circulating Angiopoietin (Angpt) levels are closely linked to increased morbidity and
mortality. Accordingly, we hypothesized that activation of the Tie2 receptor would
restore vascular quiescence and function in disease states such as diabetic
nephropathy. To test this hypothesis and test the capacity of potent on-target therapies,
we will combine studies using robust, genetic animal models, small molecule inhibitors
and proteomic strategies for defining the role of the Angiopoietin-Tie2/Tek pathway in
vascular diseases. Using these approaches, we will precisely characterize, for the first
time, the function(s) and contributions of each of the major Angpt ligands in activation of
the Tie2 receptor in the vasculature in vivo, and determine whether inhibition of the
phosphatase, VE-PTP, can activate Tie2 in vivo and protect the endothelium from injury
in a disease such as diabetes. We will also characterize the complete
phosphoproteome of Tie2 and the related ligandless-receptor Tie1, to designate
specified vascular functions and effectors for each individual phosphorylation site,
ultimately paving the way to improved drug design for vascular dysfunction. Despite the
current intense interest in the Angpt-Tie2 pathway by clinicians and pharma, large gaps
exist in our knowledge surrounding fundamental aspects of its function(s) at the whole
animal, tissue and molecular level. Our studies will provide critical new insights, which
are necessary for providing the rationale for supporting clinical applications of this
promising therapeutic target.
StatusFinished
Effective start/end date8/1/145/31/19

Funding

  • National Heart, Lung, and Blood Institute (5R01HL124120-04)

Fingerprint

Angiopoietins
Vascular Diseases
Blood Vessels
TIE-2 Receptor
Therapeutics
Drug Design
Genetic Models
Diabetes Complications
Proteomics
Endothelium
Sepsis
Cardiovascular Diseases
Animal Models
Phosphorylation
Ligands
Inflammation
Morbidity
Phenotype
Survival