CAREER: Synthetic ‘remote control’ of kidney tissue formation towards large-scale models of congenital disease

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The goal of this Faculty Early Career Development (CAREER) project is to create kidney tissues in an environment mimicking that of natural development in the body. The kidney is a hotspot for birth defects that affect the size, number, and arrangement of filtration units, called nephrons, and the tubules that carry urine within the kidney and out to the bladder. This project seeks determine the engineering rules that guide tubules as they form in the kidney and then to mimic nephron fusion with the tubule network. Together, these activities will create more "true-to-life" kidney tissues in a dish that can be used to study the origin of kidney birth defects at a fundamental level and inform new intervention strategies for childhood and adult diseases that originate from such defects. Two integrated educational projects are designed to equip a new generation of young scientists with the quantitative skills needed to contribute to the emerging discipline of “developmental engineering." The first project is creating a summer research experience for undergraduate students in which participation will be broadened by focusing recruitment efforts on under-represented minority, women, and first-generation students through several partnerships based on the investigator’s commitment to removing barriers to the use and generation of technology by all people. The second project is creating free and publicly available lesson/lecture plan modules through a crowd science platform called quanti.us. These modules will serve high school and undergraduate sciences educators and aim to stoke student interest in cutting-edge scientific problems while equipping them with quantitative problem-solving approaches.The investigator’s long-term research goal is to develop advanced biomanufacturing strategies based on the control of tissue morphogenesis with expectations that efforts will lead to the creation of human tissues with sufficient complexity to be models for drug development or directly in regenerative medicine. Toward this goal, this CAREER project is focused on mimicking nephron differentiation and fusion with the ureteric tree in synthetic tissue models of the developing kidney, which will be accomplished by generating human kidney tubule networks with controlled size and connectivity and then directing nephron formation at many spatial sites within them to better capture kidney structure at cm-scale. The project addresses the need for models of kidney development outside of the body with sufficient organization across length-scales to properly study common development diseases of the kidney such as CAKUT (congenital anomalies of the kidney and urinary tract), which is marked by incomplete organization of epithelial networks necessary for kidney function. Studies are designed to test the hypothesis that the mechanical microenvironment of kidney epithelial bud branching into the surrounding extracellular matrix (ECM) "mesenchyme" during development sculpts tubule elongation and geometric spacing. The research plan is organized under two specific aims: (1) Determine the mechanical contribution of the tissue micro-environment to epithelial tubule guidance using tissue-engineered mimics of the mesenchyme and an existing FEM model and (2) Engineer nephron integration into dynamic tissue scaffolds through spatially guided differentiation, leveraging cell patterning, biochemical, and optogenetic approaches to direct the differentiation of early nephron lineages at many specific sites in tubule networks within dynamic scaffolds at once. The ability to mimic human kidney development beyond the level of a single nephron or tubule will finally create opportunities to study and develop therapies for congenital kidney diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.