# Role of Extracellular Matrix in Retinal Development and Disease

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2021 · $150,407

## Abstract

Contact PD/PI: Brunken, William, J.
 The immediate goal of our project is to understand the role of the extracellular matrix in retinal development
and disease. In prior funding periods, we identified unique isoforms of laminins, containing either the β2 or γ3
chains that are expressed in the eye and brain. Mutations in these two laminin genes, in humans, result in
autism, ocular dysgenesis, and kidney dysfunction. Ablation of these genes, in mouse, produce cortical and
ocular dysgenesis; the latter includes disruptions of: 1) retinal ganglion cell development; 2) astrocyte migration
and subsequent vascular development; 3) the sub-cellular organization of the Müller cell; 4) the photoreceptor-
bipolar synapse. Our fundamental hypothesis is that laminins are critical for establishing the three
dimensional structure of the retina. Specifically, we hypothesize that laminins provide environmental
cues that are essential for angiogenesis and neurogenesis.
 Our first aim explores the contributions of laminin signaling in formation of the template for angiogenic
development. The working hypothesis is that RGCs drive astrocyte migration; then, interactions
between astrocytes and microglia regulate endothelial development. We will use a reverse genetic
approach, deleting Lamb2 or Lamc3 genes alone, or together, to disrupt the signaling among these cells. The
first set of experiments will focus on the spatial patterning in Lamb2-/- and Lamc3-/- animals. Our second set of
experiments will address the role of laminin-mediated recruitment and activation of microglia. The third set of
experiments will examine the effectors of laminin signaling in endothelial cells during angiogenesis. Our current
data suggest that β2-containing laminins are pro-angiogenic and γ3-containing laminins are anti-angiogenic.
 Our second aim is focused on the role of laminins in neurogenesis. We will examine the hypothesis that
laminin regulates apical-basal polarity of the radially organized progenitor. Our published data
demonstrate that Müller cell compartmentalization is disrupted in the Lamb2-/- retina. Moreover, our preliminary
data demonstrate that the cell cycle is dysregulated in both Lamb2-/- and Lamc3-/- mice. Our first set of
experiments will focus on the regulation of symmetric versus asymmetric division in the Lamb2-/- and Lamc3-/-
retina. Next, we will turn to a study of the pattern of inheritance of important cell cycle regulators in these same
mice. Last, we will measure directly the cell cycle regulation in Lamb2-/- and Lamc3-/- retina. Our preliminary
data suggest that β2- and γ3-containing laminins are necessary to preserve the proliferative state.
 Our work is relevant to an understanding of the pathobiology of retinal neovascular disease, gliosis and
proliferative vitreoretinopathy because astrocytes and microglia play critical roles in retinal vascularization and
remodeling. Our work on retinal progenitor cells will improve our fundamental understanding of reti...

## Key facts

- **NIH application ID:** 10330943
- **Project number:** 3R01EY012676-17S1
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** WILLIAM J BRUNKEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $150,407
- **Award type:** 3
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330943

## Citation

> US National Institutes of Health, RePORTER application 10330943, Role of Extracellular Matrix in Retinal Development and Disease (3R01EY012676-17S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10330943. Licensed CC0.

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