Spatial Metabolic Regulation in Kidney Repair

Introduction

Chronic kidney disease (CKD) is a global health concern, and the limited treatment options for end-stage kidney disease have remained unchanged for decades. Concurrent insults to the kidney can exacerbate disease progression, but the underlying potential to have kidney repair after such injury remains poorly understood.

Background

The tricarboxylic acid (TCA) cycle, a fundamental metabolic pathway, plays a vital role in energy production and biomolecule synthesis. Recent research by my group has revealed that failed repair and subsequent fibrosis in kidney epithelial cells are linked to anaplerotic failure in the TCA cycle, resulting in the inability to maintain sufficient levels of TCA intermediates.

Metabolic Regulation

These metabolites regulate chromatin remodeling and cell signaling pathways, influencing cell fate decisions. SPARK aims to investigate the impact of perturbed cell metabolism and metabolic crosstalk within kidney microenvironments on cell fate decisions during injury and repair.

Project Objectives

The project will:

1. Map the metabolic, proteomic, and transcriptomic interactome at an unprecedented resolution, focusing on the kidney tissue microenvironment.
2. Integrate spatial multi-omics data, exometabolite interactome analysis, and human kidney biopsies to identify actionable targets.
3. Validate the metabolic effects of the selected targets through in vivo studies using reporter mice and ex vivo preserved human kidneys.

Expected Outcomes

This research will provide insights into how the metabolic interactome governs repair through epigenetic modulations in the kidney and establish a paradigm for studying tissue homeostasis in various contexts.