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Stoller, M.

Publications and source records attributed to Stoller, M..

3 recordsLinked to original sources

Development and validation of an ultra-low-cost, open source normothermic ex vivo organ perfusion platform

BackgroundNormothermic ex vivo organ perfusion (NEVOP) promises to catalyze organ preservation, therapeutic discovery, and organ-specific disease modeling. Existing technology platforms remain inaccessible for research due to restricted access to commercial organ perfusion devices, high costs of both devices and proprietary consumables, and steep technical learning curves. Additionally, the available technology is not optimized to perfuse smaller organs such as the kidney. MethodsTo overcome these barriers, a custom NEVOP circuit was developed using recycled, repurposed, and low-cost components. Porcine kidneys and autologous blood were used to iteratively optimize circuit design. A porcine kidney autotransplantation protocol was adapted to evaluate in vivo kidney function after ex vivo perfusion. To pilot the flexibility of this system as a multi-organ platform for ex vivo human biology, non-transplantable human donor kidney, spleen, and pancreas specimens were stably perfused using human blood products and analyzed. ResultsAn ultra low-cost NEVOP system engineered to perfuse porcine kidneys and diverse human organs (kidney, pancreas, and spleen) sustained viable organs for up to 24 hours with evidence of both function and viability. Key innovations included a parallel flow resistor to facilitate low-flow perfusion in non-heparinized organs and a containment bag with adjustable magnets to provide vascular stability and recycling of venous overflow. The circuit costs less than 1,500USD to construct, and porcine kidneys perfused for 24 hours on this platform demonstrated healthy in vivo function upon autotransplantation. ConclusionsCustom NEVOP platforms constitute novel and potentially transformative research platforms which use low-cost and readily available materials. Paired with access to non-transplantable research organs from altruistic donors, this model provides a road map for investigators to advance biomedical discovery and human ex vivo biology.

bioengineering↗

Comprehensive Proteomic Quantification of Bladder Stone Progression in a Cystinuric Mouse Model Using Data-Independent Acquisitions

Cystinuria is one of various disorders that cause biomineralization in the urinary system, including bladder stone formation in humans. It is most prevalent in children and adolescents and more aggressive in males. There is no cure, and only limited disease management techniques help to solubilize the stones. Recurrence, even after treatment, occurs frequently. Other than a buildup of cystine, little is known about factors involved in the formation, expansion, and recurrence of these stones. This study sought to define the growth of bladder stones, guided by micro-computed tomography imaging, and to profile dynamic stone proteome changes in a cystinuria mouse model. After bladder stones developed in vivo, they were harvested and separated into four developmental stages (sand, small, medium and large stone), based on their size. Data-dependent and data-independent acquisitions allowed deep profiling of stone proteomics. The proteomic signatures and pathways illustrated major changes as the stones grew. Stones initiate from a small nidus, grow outward, and show major enrichment in ribosomal proteins and factors related to coagulation and platelet degranulation, suggesting a major dysregulation in specific pathways that can be targeted for new therapeutic options.

cell biology↗

A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster

Elevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumulation of UA concretions and diet-dependent shortening of lifespan. Inhibition of insulin-like signaling (ILS) pathway genes reduced UA and concretion load. In humans, SNPs in the ILS genes AKT2 and FOXO3 were associated with UA levels or gout, supporting a conserved role for ILS in modulating UA metabolism. Downstream of the ILS pathway UA pathogenicity was mediated partly by NADPH Oxidase, whose inhibition attenuated the reduced lifespan and concretion accumulation. Thus, genes in the ILS pathway represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones.\n\nHighlightsO_LIIn Drosophila high uric acid (UA) levels shorten lifespan and cause UA aggregation\nC_LIO_LIConserved in flies and humans, the ILS pathway associates with UA pathologies\nC_LIO_LIFoxO dampens concretion formation by reducing UA levels and ROS formation\nC_LIO_LIInhibition of NOX alleviates the lifespan attenuation and UA aggregation\nC_LI

pathology↗