# Role of the S100 Family of Proteins in Lens Physiology and Cataract

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $402,500

## Abstract

PROJECT SUMMARY
The ocular lens plays a crucial role in focusing incident light on to the retina, with aberrations in lens transparency
and mechanical properties leading to impairment of vision. Despite continuing effort, our understanding of the
various molecular pathways governing lens cytoarchitecture, homeostasis, deformability, clarity, and the
etiological mechanisms of cataract remains incomplete. We recently identified that several members of the S100
family of calcium binding proteins are abundantly expressed and exhibit distinct distribution profiles in the lens.
While expression of S100A6 and S100A10 distributed to both the lens epithelium and fibers, S100A4 distributes
discretely to lens fiber cells. Absence of S100A4 but not S100A6 or S100A10 leads to opalescent late-onset
cataract formation in a mouse model, together with the robust upregulation of S100A5, the expression of which
was otherwise undetectable in the wild type lens. Other than these new data on S100A4, we currently have no
knowledge of the role played by the S100 family of proteins in lens function. S100A4 is expressed in a cell and
tissue specific manner and is involved in the pathophysiology of various diseases. The physiological function of
S100A4 however, is poorly understood. A well-understood molecular function of S100A4 is its interaction with
non-muscle myosin II (NM II), especially NM IIA, and regulation of NM II assembly, actin polymerization,
contractile characteristics, cell migration, and plasticity. NM II plays a crucial role in lens cytoarchitecture,
mechanics, and function. Though NM IIA mutations are associated with cataract development in humans, little
is known about regulation of NM II activity in the context of lens function. While lenses derived from mature
S100A4 null mouse lenses (2 to 6 month old) remain clear and maintain normal growth and size, those from six
month-old mice exhibit impairments in assembly and phosphorylation of NM IIA, polymerization of actin, and
alterations in the levels of aquaporin-5, CLIC5, connexin-50, cell adhesive proteins (integrin-β1, NrCAM, ZO-1)
and α-crystallin, culminating in opalescent cataract formation in eight month-old mice. Based on these
preliminary and novel findings, we hypothesize that S100A4 plays a crucial role in regulating NM II assembly in
the lens, and that the absence of S100A4 disrupts NM II assembly and phosphorylation, actin polymerization,
mechanical properties, and osmotic homeostasis in the lens, leading to late onset cataract formation. To test this
hypothesis, in three interrelated specific aims, we will investigate: 1) the mechanistic role of S100A4 in regulation
of lens NM II assembly and phosphorylation, actin polymerization, cell adhesion, and lens tensile properties, 2)
the disruption of osmoregulation and solute carrier transport mechanisms underlying cataractogenesis in
S100A4 null lenses, and 3) the effects of rescuing expression of S100A4 in S100A4 null mouse lens fibers (using
a ...

## Key facts

- **NIH application ID:** 10893923
- **Project number:** 5R01EY034450-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** P VASANTHA RAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893923

## Citation

> US National Institutes of Health, RePORTER application 10893923, Role of the S100 Family of Proteins in Lens Physiology and Cataract (5R01EY034450-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893923. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*