The Synthetic Kidney: A Revolutionary Solution for the Shortage of Kidneys for Transplantation

项目摘要 七分之一的美国人患有慢性肾病（CKD）。当肾功能持续下降时，CKD 患者可能发展为终末期肾病（ESRD或肾衰竭）。在美国，每1000个成年人中就有2个 这些患者必须靠透析或肾移植生存。每年，更多 超过490亿美元用于治疗ESRD患者，ESRD也大大降低了寿命和生活质量 对患者与透析相比，肾移植提供了最好的生存机会，但捐赠器官很少 都是可用的。因此，迫切需要解决肾脏短缺的创新解决方案 可用于移植。目前开发肾脏替代治疗的策略面临 巨大的挑战，有限的成功。在这里，我们提出了一个完全不同的方法来生成一个 可移植肾：合成肾方法。人造肾脏是由天然的 祖细胞群体产生类似于胚胎肾的结构。合成肾脏 移植到接受者的腹部，在那里它将继续生长，分化，血管化， 通过遵循肾器官发生的正常过程原位功能成熟。拟定研究 基于我们在过去十年中扎实的技术创新。一步一步，我们有 建立了系统，以产生大量高质量的肾单位祖细胞（NPC）和输尿管 芽祖细胞（UPC）是肾脏发育的两个最重要的组成部分。我们还 成功地利用培养的NPC和UPC组装了一个体外自组织合成肾， 显示出广泛的分支、肾单位诱导、模式化和成熟。因此，我们处于独特的地位， 开展这一创新的合成肾脏项目，旨在解决肾脏短缺的问题， 移植拥有一支跨学科的研究团队，涵盖干细胞，肾脏发育， 肾脏生理学，动物模型和生物工程，我们将1）产生一个放大的可移植的合成 通过干细胞技术和生物工程策略相结合来治疗肾脏; 2）评估生长， 移植的合成肾的分化、血管化和功能成熟; 3）确定移植的合成肾的血管化、血管化和功能成熟。 合成肾在CKD和ESRD动物模型中的治疗潜力。如果人造肾的方法 可以阻止CKD的进展，并为ESRD患者提供替代器官移植， 减少CKD相关并发症和透析，从而改善患者护理并降低健康 护理费用。

PROJECT SUMMARY 1 out of 7 Americans develop chronic kidney disease (CKD). When kidney function continues to decline, CKD patients may develop end-stage renal disease (ESRD, or kidney failure). 2 out of 1000 adults in the U.S. develop ESRD and these patients must live on dialysis or get a kidney transplant to survive. Each year, more than $49 billion is spent to treat patients with ESRD and ESRD also greatly reduces longevity and quality of life for patients. Compared to dialysis, kidney transplant offers the best chance of survival, but few donor organs are available. Thus, there is an urgent need for innovative solutions that address the shortage of kidneys available for transplantation. Current strategies towards developing a kidney replacement therapy face significant challenges with limited success. Here we propose a radically different approach to generating a transplantable kidney: the synthetic kidney approach. The synthetic kidney is engineered from native progenitor populations to generate a structure similar to the embryonic kidney. The synthetic kidney is then transplanted into the abdomen of the recipient, where it will continue to grow, differentiate, vascularize and functionally mature in situ by following the normal process of kidney organogenesis. The proposed study is based on our solid technological innovations over the course of the past decade. Step by step, we have established systems to generate large quantities of high-quality nephron progenitor cells (NPCs) and ureteric bud progenitor cells (UPCs), the two most important building blocks for a developing kidney. We have also succeeded in using cultured NPCs and UPCs to assemble an in vitro self-organizing synthetic kidney, which shows extensive branching, nephron induction, patterning, and maturation. We are thus uniquely positioned to carry out this innovative synthetic kidney project with the goal of solving the shortage of kidneys available for transplantation. With an interdisciplinary research team covering expertise of stem cell, kidney development, kidney physiology, animal models and bioengineering, we will 1) generate a scaled-up transplantable synthetic kidney by combining stem cell technologies and bioengineering strategies; 2) evaluate the growth, differentiation, vascularization, and functional maturation of the transplanted synthetic kidney; 3) determine the therapeutic potential of the synthetic kidney in CKD and ESRD animal models. If the synthetic kidney approach can halt CKD progression and provide alternative organ transplants for ESRD patients, there will be a dramatic reduction in CKD-related complications and dialysis, thereby improving the patient care and reducing health care costs.