# Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $410,000

## Abstract

Corneal neovascularization greatly increases the risk for corneal graft rejection, and thus contributes to
severe vision loss, risk of endophthalmitis, and life-threatening meningitis. It afflicts up to 1.4 million new
patients annually and together with other pathological angiogenesis is the leading cause of blindness in the
United States. Angiogenesis also contributes to diseases that range from cancer to arthritis. A wide range of
protein growth factors (e.g. VEGF, bFGF, PDGF) stimulate angiogenesis, but only VEGF is currently targeted
for antiangiogenic therapy in the eye. CMG2 is an integrin-like transmembrane protein with an extracellular
domain that binds ECM proteins and an intracellular tail without homology to domains of known function. We
find that targeting CMG2 via the protein inhibitor PASSSR, CMG2-binding small molecules, or CMG2 knockout
profoundly inhibits corneal neovascularization, but the mechanism underlying this effect is unknown.
 Angiogenesis requires endothelial cells to migrate towards growth factors. This migration has both a
movement component (motility = chemokinesis) and a directional component (chemotaxis). However, these
components cannot be distinguished using traditional (wound scratch or transwell) assays. Using a microfluidic
migration assay that tracks individual cells over time, we recently discovered that CMG2 targeting completely
disrupts chemotaxis, but not chemokinesis. This effect is observed with multiple growth factors (bFGF, VEGF,
PDGF) and all targeting methods tried thus far (CRISPR knockout, PASSSR, blocking peptide). Thus, we
hypothesize that CMG2 is a key intermediary in a pathway required for growth-factor induced chemotaxis and
efficient angiogenesis. We will test this hypothesis by: 1) identifying intracellular interactions required for
CMG2-mediated chemotaxis; 2) identifying extracellular interactions required for CMG2-mediated chemotaxis
in response to growth factors, and 3) evaluating the contribution of RhoA to CMG2-directed chemotaxis.
 Our working model of CMG2 signaling is based on preliminary data from our lab and others that indicates
that CMG2 localizes near RhoA and several Rho pathway members. Thus, CMG2 is positioned to directly
regulate the cell polarity required for directional migration (chemotaxis). Indeed, we observe that inhibiting
RhoA phenocopies CMG2 inhibition. Finally, we can bypass CMG2 signaling by activating RhoA via the S1P
receptor, so that chemotaxis is no longer sensitive to CMG2 targeting. Thus, RhoA is downstream of CMG2.
 Successful completion of proposed work will identify the mechanism underlying the strong antiangiogenic
effects observed upon CMG2 targeting in vivo and accelerate exploitation of this potential target for broad-
spectrum antiangiogenic therapy. In addition, this work will enable the development of pharmacodynamic
assays to rapidly evaluate drug leads. Finally, key aspects of this proposal are designed to produce possible
therapeutic leads. ...

## Key facts

- **NIH application ID:** 10522258
- **Project number:** 1R01EY033354-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MICHAEL SEAN ROGERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2022-09-30 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522258

## Citation

> US National Institutes of Health, RePORTER application 10522258, Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis (1R01EY033354-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10522258. Licensed CC0.

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