# Endothelial Transmigration in Neovascular Age-related Macular Degeneration

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

The pathophysiology of neovascular age-related macular degeneration (nvAMD) is complex and
involves the impact of genetic predisposition, environmental stresses and advanced aging on
signaling events that overwhelm retinal/choroidal homeostasis and enable activation and migration of
Choroidal Endothelial Cells (CECs) across the Retinal Pigment Epithelial (RPE) cell monolayer into
neural retina to become Choroidal Neovascularization (CNV). Using physiologically relevant human
heterotypic cocultures to model RPE/CEC interactions, we now focus on mechanisms necessary for
CEC transmigration of the RPE, including crosstalk among activated signaling pathways in CECs that
involve angiogenic (VEGF and CCR3), inflammatory (TNFα), and oxidative factors that feed-forward
to induce Rac1-dependent CEC migration. In particular, our findings -- that (i) the scaffolding protein
IQGAP1 that brings together multiple signaling cascades to enable biologic events to occur, is
necessary for CEC transmigration, together with (ii) Thy-1 is overexpressed in CECs from older eyes
and eyes exposed to AMD-related factors -- support the following hypothetical framework that will be
tested in the next funding period: that (1) complex intracellular signaling cascades may be linked
together to a) activate CEC migration through the IQGAP1 GRD domain, to enable Rac1-mediated
CEC activation and b) enable CEC migration via ECm-induced Thy-1/IQGAP1 interactions with ECm,
and that 2) IQGAP1-facilitated pathologic signaling might be inhibited when activated Rap1a binds to
the IQGAP1, thus restoring CEC quiescence and preventing CNV. Specific Aim 1 is to test the
prediction that Rac1/IQGAP1 binding affects CEC activation and migration induced by AMD-related
ligands involving angiogenesis, inflammation and oxidation. Specific Aim 2 is to test mechanistic
roles of Rap1/IQGAP1 binding on CECs and CNV formation. Specific Aim 3 is to test mechanisms
underlying Thy-1/IQGAP1 interactions in activating CECs and enabling CNV formation. Tools include
isolated human CECs; mutant constructs to different IQGAP1 domains that inhibit direct binding of
the GTPases Rac1 or isoforms of Rap1 (to test predictions regarding induced CEC migration);
engineered adenoviral constructs (to introduce constitutively active, dominant-negative or wild type
Rap1 isoforms or Rac1), or microRNAs (to test mechanisms of action); pharmacologic agents that
activate Rap1; and knockout mice to Rap1 isoforms and IQGAP1 (to test mechanisms involved in
laser-induced CNV with the Micron IV); These studies will test whether Rap1 binding to IQGAP1
inhibits steps necessary for CNV formation and restores CECs to a quiescent state. Results will
inform future research on therapies to target multiple causal events in CEC activation and migration in
nvAMD and restore CEC quiescence while reducing risks of current angiogenic inhibitor treatments.
!

## Key facts

- **NIH application ID:** 9873040
- **Project number:** 5R01EY017011-15
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Mary Elizabeth Ruth Hartnett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2005-12-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873040

## Citation

> US National Institutes of Health, RePORTER application 9873040, Endothelial Transmigration in Neovascular Age-related Macular Degeneration (5R01EY017011-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873040. Licensed CC0.

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