# Cellular and molecular mechanisms governing bladder aging.

> **NIH NIH R56** · BAYLOR COLLEGE OF MEDICINE · 2024 · $400,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Bladder conditions such as incontinence and urinary tract infections (UTI) are increasingly common with aging
and driven by poorly understood changes that occur at the cellular and molecular levels. The objective of this
project is to define the molecular pathways that underpin how aging makes the bladder epithelium (urothelium)
prone to UTIs and develop new therapeutics to target those pathways. Data indicate that IFRD1 plays a key role
in ribosomal quality control, translation, ER trafficking, and ER stress; and loss of IFRD1 produces aging
phenotypes. The central hypothesis is that aging disrupts the cellular function of proteostasis, particularly
ribosome dynamics during protein translation, modification, and trafficking between the ER and Golgi. Aim 1 will
determine the role of ribosomal and translational quality control machinery in the maintenance of bladder
homeostasis in young, aged, or Ifrd1−/− urothelium of mice. Cycloheximide treatment will be used to inhibit
translation in young mice, and translation efficiency will be quantified with a puromycinylation assay to test if
treatment is sufficient to induce phenotypes of aging or Ifrd1−/− bladders. UTI will be induced using uropathogenic
E. coli., and bladder tissue will be collected to assess molecular-cellular and inflammatory responses using
histological analysis, western blots, and qRT-PCR to measure expression of ribosome-associated quality control
markers and IFRD1 expression. To determine urothelial-intrinsic role, we will use a newly generated state of the
art 3D- murine urothelial organoid system, with the potential to extend investigations to a human urothelial
organoid system. Aim 2 will determine whether chronic ER stress is sufficient for promoting aging phenotypes,
and if alleviating ER stress will ameliorate the phenotypes. In aged, young, and Ifrd1−/− mice bladders and
organoids, the expression of ER stress proteins and uroplakins will be compared. Western blots, qRT-PCR, and
immunostaining will be used to determine if uroplakin trafficking is altered in aged bladders, as in the Ifrd1−/−
phenotype. Inflammation, DNA damage, lysosomes, mitochondria, urothelial cell shedding, and expression of
ER stress response proteins will be assessed in response to the ER-stressor tunicamycin and ER stress
alleviator TUDCA to determine if this stress drives aging in the urothelium using organoid models. Aim 3 will
determine the effects of pharmacological interventions on aging bladder and identify novel proteins governing
bladder aging. Understanding the effects and mechanism of action in these drugs will establish a foundation on
which translational research can work to develop novel interventions for the treatment of urinary tract conditions
that are known to progress with age.

## Key facts

- **NIH application ID:** 11170829
- **Project number:** 1R56AG084691-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jason C Mills
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2024-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11170829

## Citation

> US National Institutes of Health, RePORTER application 11170829, Cellular and molecular mechanisms governing bladder aging. (1R56AG084691-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11170829. Licensed CC0.

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