# Study of melanocyte lineage through SASH1 and associated proteins

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $384,705

## Abstract

PROJECT SUMMARY
 Pigmenting cells (melanocytes) protect vital stem cells and subcutaneous tissues from ultraviolet
radiation, and melanocyte stem cells sustain a healthy population of melanocytes through life. Dysregulation
of melanocytes (MCs) or melanocyte stem cells (McSCs) leads to diseases that significantly affects an
individual's quality of life, including hyper- and hypo-pigmentation disorders, and fatal cancer. Currently,
much is still undefined about the molecular mechanisms for many pigmentation disorders or for controlling
melanocytes or melanocyte stem cells. Our long-term goal is to better understand the biology and pathology
of McSC/MC, and to explore how McSC/MC can be manipulated for preventive and therapeutic purpose.
The objective here is to study the proliferation, differentiation and maintenance of the MC lineage through
dissecting the functions of SASH1 and its associated proteins. The rationale for our proposal is that SASH1
is a novel and not well characterized gene involved in MC/McSC and pigmentation, and therefore
understanding its relevant functions will likely lead to new potential approaches and targets for manipulating
McSC/MC to treat MC-related diseases.
 We identified a mutation in SASH1 (S519N) as causative for an inherited hyper-pigmentation disorder.
Based on our data and literature, we hypothesize that SASH1 plays a critical role in proliferation,
differentiation and maintenance of the melanocyte lineage. We also propose that SASH1S519N disrupts
mitotic function and differentiation of these cells, resulting in the pigmentation disorder. To test our
hypotheses, Aim 1 will define the molecular mechanisms of SASH1 in proliferation and differentiation of
McSC/MC with the patient-specific induced pluripotent stem cell (iPSC) model. We will generate patient-
specific iPSC clones from SASH1S519N individuals, and then construct gene-corrected and null isogenic
clones with the CRISPR/Cas system. Using the iPSCs, as well as McSCs and MCs derived from these
clones, we will define the proliferation and differentiation kinetics of SASH1 variants, and exam the
underpinning molecular mechanism for SASH1's functions in melanocyte lineage. We have identified
several binding partners for SASH1. We will further investigate their functional relevance to SASH1's roles
in the melanocyte lineage with genetic, biochemical, molecular, and cellular biological approaches. Aim 2
will use mouse model to study the function of SASH1 in maintenance of the melanocyte lineage. We will
test how SASH1 loss affects proliferation and differentiation of these cells using SASH1 knockout mice.
Thus, we expect our work will have a positive impact with new insights into the mechanisms and new
regulators in the fields of MC and McSC biology along with diseases research associated with these cells.

## Key facts

- **NIH application ID:** 10596208
- **Project number:** 5R01AR074420-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Yiqun G Shellman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $384,705
- **Award type:** 5
- **Project period:** 2020-04-13 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596208

## Citation

> US National Institutes of Health, RePORTER application 10596208, Study of melanocyte lineage through SASH1 and associated proteins (5R01AR074420-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10596208. Licensed CC0.

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