# Molecular Mechanisms of Pigmentation in Health and Disease

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2020 · $342,000

## Abstract

PROJECT SUMMARY / ABSTRACT
 Melanin pigments are responsible for pigmentation of skin hair and eyes and are synthesized in an organelle called
melanosome in melanocytes and retinal pigmented epithelial cells. In the case of skin melanocytes, melanin pigments are
then transferred to neighboring keratinocytes. Examples of pigmentation disorders characterized by defective melanosome
biogenesis and function include Hermansky-Pudlak syndrome, oculocutaneous albinism and Griscelli syndrome. Further,
the sequestration and secretion of intracellular cytotoxic drugs by melanosomes underlies the development of multidrug
resistance in melanomas. Consequently, inhibiting melanosome function constitutes an important approach to enhance the
chemosensitivity of melanoma cells. Thus, understanding the molecular mechanisms regulating pigmentation has
physiological significance and will likely lead to clinical applications. In spite of the relevance of pigmentation for human
health, there are significant knowledge gaps in our understanding of melanosome biogenesis and function. Our goal is to
answer fundamental outstanding questions in this area of the pigmentation field in an integrated manner and focusing on
molecular mechanisms.
 Aim 1: The enzymes tyrosinase, tyrosinase-related protein 1 (Tyrp1) and Tyrp2 synthesize melanin in the
melanosome lumen. Melanosome biogenesis requires the delivery of the three melanogenic enzymes to the maturing
organelle. The transport of newly synthesized tyrosinase and Tyrp1 to melanosomes is relatively well understood. In
contrast, the pathway followed by Tyrp2 to melanosomes is unknown. We have evidence that Tyrp2 uses a different
transport route from the one used by tyrosinase and Tyrp1. We will utilize a novel assay we recently developed to define
the pathway followed by Tyrp2 and compare it with the pathway used by tyrosinase and Tyrp1. The biogenesis of
melanosomes (and other lysosome-related organelles) depends on the function of several proteins that are encoded by
genes mutated in various forms of Hermanky-Pudlak syndrome (HPS). The two most common and severe forms of the
disease are HPS1 and HPS4, yet little is known about the function of these HPS proteins in organelle biogenesis. We will
test the hypothesis that HPS1 and HPS4 together with the small GTPase Rab32 define a transport pathway to
melanosomes that is used by Tyrp2 and other melanosomal proteins. Aim 2: A genome-wide association study identified
Two-Pore Channel 2 (TPC2) as a genetic determinant of pigmentation but how TPC2 regulates pigmentation is a mystery.
Our data suggests TPC2 is a component of the melanosome membrane that regulates melanosome function. We will test
the hypothesis that through changes in melanosome pH, TPC2 controls the activity of the tyrosinase enzymes and the
amount and type of melanin synthesized. Moreover, we will study the mechanism of TPC2 function and polymorphisms
associated with pigmentation variations. Aim 3: After melanosom...

## Key facts

- **NIH application ID:** 9843678
- **Project number:** 5R01GM125619-03
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Santiago Mauro Di Pietro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843678

## Citation

> US National Institutes of Health, RePORTER application 9843678, Molecular Mechanisms of Pigmentation in Health and Disease (5R01GM125619-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9843678. Licensed CC0.

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