# Investigating Membrane Trafficking Deficits in Choroideremia

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $237,610

## Abstract

SUMMARY: Death of the choroid, the vascular bed underlying the retina, is a prominent pathologic hallmark of
numerous inherited retinal degenerative diseases as well as age-related macular degeneration (AMD).
Choroidal death is likely impacted by dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells
between the photoreceptors and the choroid. A critical knowledge gap impeding progress in therapeutic
strategies is how RPE dysfunction contributes to choroidal death. Choroideremia is an inherited chorioretinal
degeneration leading to early blindness with no current treatment. Several lines of evidence implicate the RPE
as the primary site of degeneration, with secondary degeneration of the photoreceptors and choroid. The
causative genetic defect is deficiency of CHM, encoding Rab escort protein 1 (REP-1), which facilitates
prenylation of Rab GTPases, a critical step in membrane trafficking. RPE cells are highly polarized and
differentially secrete numerous growth factors and signaling molecules in a directional manner towards the
photoreceptors and choroid. The proposed studies will elucidate how RPE membrane trafficking defects in
choroideremia alter protein secretion and how this impacts choroidal survival. The long-term goal of this work
is to develop the necessary skills and expertise to establish an independent career focused on therapies
targeting RPE dysfunction in retinal degenerative disease. The scientific objective is to understand
mechanisms of choroidal death. We will test the hypothesis that alterations in RPE secretion of proteins in the
vascular survival pathway lead to choroidal atrophy in choroideremia using a human stem cell derived RPE
model. The career development objectives are to master stem cell culture and RPE derivation techniques, to
develop expertise in membrane trafficking pathways of RPE, to become proficient in the techniques and
principles of therapeutic target discovery, and to develop skills in leadership, mentorship, and scientific
communication necessary to become a successful independent investigator. The proposed study will increase
the candidate’s understanding of choroideremia and identify therapeutic targets in this untreatable blinding
disease, which may also have broader implications for choroidal degeneration in AMD and other chorioretinal
degenerative diseases.

## Key facts

- **NIH application ID:** 10469438
- **Project number:** 5K08EY032991-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Abigail Fahim
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,610
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469438

## Citation

> US National Institutes of Health, RePORTER application 10469438, Investigating Membrane Trafficking Deficits in Choroideremia (5K08EY032991-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469438. Licensed CC0.

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