# Molecular and Cellular Pathobiology of Stone Forming Papillae

> **NIH NIH P01** · UNIVERSITY OF CHICAGO · 2020 · $293,254

## Abstract

During the last funding cycle, the PPG made significant advances in our understanding of the mechanisms of 
stone formation and growth. Project 3 has made a comprehensive and essential histopathological 
characterization of the papillae in human stone disease, and distinguished two main phenotypes that are 
essential to the pathogenesis of stone disease: plaque deposition and intratubular crystal plugging. A grasp of 
the contribution of each of these phenotypes to the type of stone disease is essential to understand the 
underlying pathology, and eventually developing targeted therapies. Achieving this objective requires the 
performance of unprecedented, detailed, studies of the various microenvironments within the human papillae 
of stone forming patients. The aims in the current proposal are designed to perform such in-depth 
investigations of the cellular and molecular mechanisms underlying these key events, using state-of-the-art 
methodology and skills of the research team. 
The role of interstitial calcium concentration in the formation of plaque is a fundamental concept. Aim 1 will 
firmly establish the importance of increased interstitial calcium in the papilla on the pathogenesis of plaque. 
Aim 2 will investigate the role of innate immune activation in plaque formation. Key downstream effects of 
innate immunity, such as oxidative stress, inflammatory signaling and crystal modulator deposition will be 
carefully studied. This aim is expected to define with high confidence, the role of inflammation in the 
pathogenesis of plaque deposition in human stone disease. 
Aim 3 will investigate a key mechanism of how plugging disease propagates in the papilla, by determining if 
ducts with plugs can stimulate oxidative stress and inflammatory signaling beyond the area contiguous to 
plugging. This cross -talk could lead to upregulation of adhesion molecules that facilitate more plugging in 
neighboring ducts. Finally, Aim 4 will investigate the rarely-studied papillary urothelium, by establishing if 
overgrowth of new stones over plaque is preceded by dysfunction of the overlying papillary urothelium. 
Methods used in these investigations will include: laser micro-dissection, 3 dimensional imaging of the papillae 
using confocal microscopy, tissue cytometry, state-of the art protein analysis and redox proteomic assays. 
Combined together, and in synergy with aims from project 1 and 2, these new aims, will greatly advance our 
understanding of the precise mechanisms of stone formation and growth, which will hopefully translate into 
more effective clinical treatments for stone disease.

## Key facts

- **NIH application ID:** 9990792
- **Project number:** 5P01DK056788-19
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Tarek Maurice Ashkar
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,254
- **Award type:** 5
- **Project period:** 2000-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990792

## Citation

> US National Institutes of Health, RePORTER application 9990792, Molecular and Cellular Pathobiology of Stone Forming Papillae (5P01DK056788-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990792. Licensed CC0.

---

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