# Ultrastructural Analysis of a Form of Macular Degeneration - Macular Telangiectasia

> **NIH NIH R21** · HARVARD UNIVERSITY · 2022 · $102,269

## Abstract

Little is known about the cellular interactions within the human macula/fovea. This is especially true for
interactions between retinal glial cells and retinal neurons – interactions likely important to understanding
retinal degenerative diseases including Macular Telangiectasia (MacTel), a form of age-related macular
degeneration (AMD) in which it has been proposed that a defect in the Müller glial cells may be at play. Müller
glia cells are relied upon to regulate ionic balance and neurotransmission, maintain metabolic stasis, constitute
the blood-retinal barrier, among multiple other essential neuroprotective functions. An increasing focus has
been on the dependence of retinal neurons on Müller cell based L-serine biosynthesis since retinal neurons (as
do neurons throughout the CNS) lack the rate limiting biosynthetic enzyme PHGDH. L-serine synthesis is
essential for lipid metabolism and maintenance of mitochondrial function. Not only have metabolomics studies
implicated alterations in the L-serine metabolic pathway in the development of MacTel but genome-wide
association/GWAS studies have linked alterations in the PHGDH gene with early onset MacTel. Not
surprisingly, alterations in the normal relationships between neurons and glial cells feature prominently in
maintaining normal retinal function and are implicated in the etiology of multiple forms of retinal degeneration.
In recent years, electron microscopic (EM) techniques have been developed such that it is now possible to
reconstruct pieces of retinal tissue down to the membrane level. Termed connectomics, it is possible to cut and
collect on tape, thousands of serial sections, and image specific regions of the sections with an EM that has
multiple beams, allowing for 61 images to be obtained simultaneously. Software methods for aligning the
images into a single 3D volume have also been developed. To date, this connectomics approach has not
been applied to gaining an understanding of pathological changes that underlie retinal degenerative
diseases. The first aim in our current proposal is to determine the structural features/changes in glial-neuronal
relationships and mitochondrial health involved in MacTel. These studies will focus especially on the cristae
structure of mitochondria, mitochondrial degradation, and the relationship between Müller cells and the
photoreceptor axons and synaptic terminals. We have made significant progress in making the typically lengthy
connectomics workflow more efficient and tailored to analyzing the basis of a neurodegenerative disease.
Using our targeted high-throughput connectomics approach our second aim is to perform parallel analysis of
our genetically similar 79-year-old donor eye and other retinas using methods refined from our experience
working with our 48-year-old donor eye. In summary, we are confident that our targeted high-throughput
connectomics approach will enable us to efficiently extract relevant ultrastructural data from multiple disea...

## Key facts

- **NIH application ID:** 10616075
- **Project number:** 3R21EY030255-02S1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** JOHN E DOWLING
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $102,269
- **Award type:** 3
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10616075

## Citation

> US National Institutes of Health, RePORTER application 10616075, Ultrastructural Analysis of a Form of Macular Degeneration - Macular Telangiectasia (3R21EY030255-02S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10616075. Licensed CC0.

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