# Rhythmic pace-making of nephron induction for renal replacement tissues > **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $700,619 ## Abstract PROJECT SUMMARY The goal of this proposal is to study and control rhythmic nephron induction for kidney replacement tissues. Kidney organoids derived from human induced pluripotent stem cells (iPSCs) re-create an astonishing cellular diversity comparable to the early fetal kidney. However, barriers remain to their implementation for regenerative medicine, chiefly the staggering volume of properly ‘plumbed’ tissue that would be necessary for functional replacement. This creates an urgent need to achieve scale-up of nephron generation. The kidney achieves scale-up during its development through an exponential increase in the number of nephron-forming ‘niches’ associated with the branching tips of the future urinary collecting duct tree. However, organoids generate nephrons in a single wave, failing to capture rhythmic, exponential nephron production from self-sustaining niches. Our long-term goal is to construct ‘higher-order’ synthetic kidney tissues using human stem cell, cell engineering, and assembly technologies that mimic the outcomes of morphogenesis. Our overall objective here is to gain temporal control over rhythmic nephron formation. Achieving this will mark a transformative advance toward creating replacement kidney tissue and in fundamental understanding of low nephron endowment, a risk factor for hypertension and chronic kidney disease. Our central hypothesis is that the periodic avalanche-like commitment of nephron progenitors to new nephrons is governed by a rhythmic ‘pace-maker’ across several signaling pathways. We plan to achieve our objective through two specific aims. Firstly, we will determine pace-making coordination across cell types in the mouse nephrogenic niche. We will expand from our preliminary spatial RNA sequencing data that discovered rhythmic alternating phases of nephron progenitor differentiation and renewal in each niche. This will define a spatiotemporally resolved map of cell-cell interactions contributing to nephrogenesis pace-making. Second, we will synthetically engineer pace-making and the nephrogenesis chain-reaction in human iPSC-derived organoids. We will program rhythmic nephrogenesis in iPSC-derived nephron progenitors using optogenetics technology and by leveraging intrinsic molecular clock dynamics. The proposed research is innovative because we co-opt our discovery of cyclical nephrogenesis signaling for novel engineering control strategies, while creating tissues that are compatible with patient-derived autologous cells for future transplantation. The proposed research will have significant positive impact in two areas: 1) Scale-up of human kidney tissue will create a step-change in renal replacement technology beyond dialysis, transplant, and “abiotic” filtration. 2) New discoveries in rhythmic nephron patterning will inform actionable approaches to improve persistence of nephrogenesis and increase nephron endowment in neonates. ## Key facts - **NIH application ID:** 10938882 - **Project number:** 1R01DK140070-01 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** Alex Hughes - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $700,619 - **Award type:** 1 - **Project period:** 2024-08-19 → 2028-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10938882 ## Citation > US National Institutes of Health, RePORTER application 10938882, Rhythmic pace-making of nephron induction for renal replacement tissues (1R01DK140070-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10938882. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*