# Understanding the Mechanisms and Consequences of Basement Membrane Aging in Vivo

> **NIH NIH F32** · DUKE UNIVERSITY · 2022 · $67,582

## Abstract

Project Summary
Basement membranes (BMs) are thin, dense, specialized extracellular matrices built on laminin and type IV
collagen scaffoldings that underlie and surround most animal tissues. BMs harbor over 100 proteins and
provide mechanical, barrier, and signaling support for tissues. Defects in BM assembly and regulation cause
embryonic lethality and are linked to numerous human diseases. Aging BMs accumulate type IV collagen and
progressively thicken, which is associated with declining tissue function, such as reduced blood flow, vision,
hearing, and stem cell renewal. The mechanism(s) driving collagen accumulation and BM thickening during
aging, however, are unclear. Furthermore, it has not yet been possible to establish whether and how collagen
accumulation causes tissue decline. A key gap in the understanding of BM aging is a lack of animal models
that allow visualization of individual BM component accumulation and turnover during aging, as well as the
ability to manipulate the levels of BM components and establish their effects on tissue function. The overall
objective of this proposal is to develop C. elegans as a powerful new model to elucidate mechanisms of BM
aging and its consequences on tissue function. C. elegans offers unique advantages for studying BM aging—a
short lifespan (~two weeks), tissue decline during aging is well characterized, all tissues are accessible to live
imaging, and facile conditional gene knockdown and overexpression approaches. In addition, most BM
components have been endogenously tagged with the genetically encoded fluorophore mNeonGreen (mNG)
(~60 BM genes) and core components with mEos2 (photoconvertible), allowing for comprehensive
examination of BM component levels and turnover of key components. Preliminary studies have revealed that,
similar to vertebrates, collagen IV accumulates dramatically in BMs (as much as 9-fold) on multiple tissues as
C. elegans age. Additionally, preventing collagen accumulation via RNAi slows the decline of the germline
stem cell niche. To determine the mechanisms and consequences of BM aging, the following specific aims
will be pursued: (1) using fluorescent recovery after photobleaching (FRAP), photoconversion, and screening
of collagen regulators, the mechanism(s) of collagen IV accumulation in aging BMs will be determined, (2)
using RNAi to deplete collagen and examining markers of tissue health and decline, the role of age-dependent
BM collagen IV accumulation in stem cell renewal, oocyte quality, ovulation, fertility, and muscle decline will be
established, and (3) using a comprehensive toolkit of endogenously tagged BM components, a BM aging atlas
will be generated that reveals how BM components change in abundance on all major tissues during aging.
The proposed research is significant, as it will establish a new model to study BM aging, elucidate how BM
collagen IV accumulates during aging and its effects on tissue decline, and create a comprehensive atlas of
BM agi...

## Key facts

- **NIH application ID:** 10465010
- **Project number:** 1F32AG077907-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** William David Ramos-Lewis
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465010

## Citation

> US National Institutes of Health, RePORTER application 10465010, Understanding the Mechanisms and Consequences of Basement Membrane Aging in Vivo (1F32AG077907-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465010. Licensed CC0.

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