# Function of a lens protein betaA3/A1-crystallin in astrocytes

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $397,500

## Abstract

Project Summary:
The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently
regressing after the formation of retinal vessels. The failure of the fetal vasculature to regress leads to serious
problems with vision, a condition known as persistent fetal vasculature (PFV) disease. The exact prevalence of
PFV is unknown; however, a study on childhood blindness and visual loss in the United States showed that
PFV accounts for 5% of all childhood cases of blindness. A major finding from our previous studies on PFV is
that astrocytes abnormally migrate into the vitreous and ensheath the hyaloid artery, suggesting a direct cause
and effect relationship between astrocyte association and vascular retention. Astrocytes are not known to be
involved in either the formation or regression of the hyaloid artery. Our data suggested that the defective
lysosomal function in astrocytes is linked to increased astrocyte migration and ensheathment of the hyaloid
artery. Several mouse models of PFV, in addition to those we have studied, appear to have astrocytes
associated with the persistent hyaloid artery. Importantly, we have also shown that astrocytes abnormally
ensheath the hyaloid artery in clinical specimens from PFV patients. PFV involves persistence of components
of the normally transient fetal intraocular vasculature and can vary widely in terms of completeness and
severity. While increased vascular endothelial growth factor (VEGF) in the vitreous is certainly an important
factor in the etiology of severe PFV, it is likely not the case in mild or moderate PFV. Our focus in this proposal
is to develop a therapy for mild/moderate disease. PFV is a complex and heterogeneous disease and no single
therapy is likely to be effective for all patients. Appropriate treatment may well depend upon disease severity.
With severe disease with a fibrotic stalk, the drug(s) that we develop here may be efficacious if given prior to
vitrectomy, analogous to anti-VEGFA injections being given prior to vitrectomy for diabetic traction detachment
to make the surgery technically simpler with reduced intraoperative and postoperative hemorrhaging. Here we
will test the hypothesis that “restoring normal astrocyte function is an effective therapeutic strategy for
PFV disease”. This objective will be accomplished by pursuing the following Specific Aims: Specific Aim 1:
To demonstrate if A1-crystallin overexpression can rejuvenate astrocyte function and thereby rescue the
PFV-like phenotype; Specific Aim 2: To test if inhibiting gefitinib and activating autophagic lysosomal
reformation triggers normal regression of the hyaloid vasculature and Specific Aim 3: To identify factors
released by A1 KD astrocytes that could inhibit normal developmental remodeling (regression) of the fetal
vasculature. The proposed study is significant because we now have the appropriate animal models to test
novel therapeutic approaches to treat PFV based on our stu...

## Key facts

- **NIH application ID:** 10366476
- **Project number:** 1R01EY032516-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Debasish Sinha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366476

## Citation

> US National Institutes of Health, RePORTER application 10366476, Function of a lens protein betaA3/A1-crystallin in astrocytes (1R01EY032516-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10366476. Licensed CC0.

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