# A Novel Metabolic Pathway Regulates Urinary Tract Infections in the Bladder

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $235,000

## Abstract

PROJECT 3: PROJECT ABSTRACT/SUMMARY
Urinary tract infections are the most common medical problem in Urology, and one of the most pervasive medical
illnesses. Patient presentation falls along a spectrum of intensive, lower urinary tract symptoms, to transient less
defined discomfort and non-diagnostic urinary findings. We believe the spectrum of presenting symptoms results
from different sites of colonization of bacteria and different levels of virulence at those sites. Our preliminary data
indicates the bacterial tropism and virulence is directly related to the capacity of bacteria to obtain nutrients, and
the most coveted substance is iron. Iron is a “precious metal” for bacteria because all metabolic processes,
including energy production and cell division requires 100,000 atoms per bacteria. The urinary system is a
particularly intriguing site of iron acquisition, because while the urine fluid contains only Nano-Molar iron content,
the urine also contains 106 red blood cells/day, containing 109 heme iron atoms each. In this setting of iron
starvation, yet potentially heme-iron abundance, bacteria can rapidly deploy tools to transfer iron from
mammalian proteins, and from heme rings directly across their membrane. We propose that this setting is
dominated by heme iron, and that heme transport systems take priority initially in stealing our iron. This
hypothesis not only derives from analysis of bacterial gene expression, but also our study of the epithelial
response to the invasion of the bladder. By creating novel tools to isolate snapshots of nascent RNA, we
discovered that the urothelium and specialized cells elsewhere in the urinary system activate their own system
of heme capture, heme metabolism, and iron sequestration. These activated mammalian pathways are of great
interest because of the immediacy of their responses, the recruitment of novel heme transporters at the site of
bacterial attack, and the production of the heme product, Carbon Monoxide, a bacteriostatic agent. In addition,
these pathways not only decontaminate heme, but they are the core complex of the Circadian Clock. We are
cognizant that the implications of these findings will require considerable research, but they include our finding
that the apical membrane of the bladder, the urothelium, can transport heme with a novel mechanism and the
realization that bacteria stimulate this process as a mechanism of innate immune defense known as nutritional
immunity. As a result of these mechanisms, we found that night time and day time UTI generate different
biological outcomes. In this renewal proposal for Project 3 of the Columbia University George M. O’Brien Urology
Research Center we go back to basic iron biology and we carefully document heme and iron transport across
the bladder, cell and bacterial responses using novel imaging tools and novel iron and CO capture tools, mouse
ko’s and bacteria carrying mutations in iron pathways that are critical in mice and human infection...

## Key facts

- **NIH application ID:** 10022311
- **Project number:** 5U54DK104309-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** JONATHAN M. BARASCH
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,000
- **Award type:** 5
- **Project period:** 2014-09-24 → 2021-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022311

## Citation

> US National Institutes of Health, RePORTER application 10022311, A Novel Metabolic Pathway Regulates Urinary Tract Infections in the Bladder (5U54DK104309-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10022311. Licensed CC0.

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