Investigating endothelial cell and glomerular anastomoses to advance kidney tissue engineering

 描述(由申请人提供)：这份K08导师职业发展申请表描述了我完成内科科学家培训的四年计划，将学术肾病实践与与肾脏疾病相关的外部资助研究项目相结合。更具体地说，我建议开发一个研究项目和必要的技能，以成为一名在肾脏组织工程领域工作的独立研究员。在纽约大学获得医学博士学位，并在耶鲁大学获得内科住院医师和肾脏病研究员资格后，我仍然强烈希望从事影响临床问题的研究。我目前是耶鲁大学内科的一名讲师。这一K08奖项将支持以下目标：1)进行肾脏组织工程研究；2)发展组织工程和微流体方面的专业知识；3)发展独立的研究事业。终末期肾病是一个重要且昂贵的问题，最好的治疗方法是肾移植。然而，供体器官严重短缺，这可能会通过组织工程肾组织来缓解。肾脏的功能单位被称为肾单位，它有三个主要组成部分：1)血液供应，2)被称为肾小球的过滤单位，以及3)在排泄之前处理滤液的小管。初步结果表明，在体内将内皮细胞与分离的肾小球种植可导致微血管和肾小球的吻合和灌流。[这里提出的研究试图进一步了解这些吻合，以显著推进这一肾组织工程策略。目的1研究肾小球在体外和体内促进内皮细胞-肾小球吻合的作用。从这些研究中获得的知识可能会显著提高吻合口的效率，并最终提高肾小球的存活率和功能。目的2是设计一种可灌流的微流体装置，通过微血管网络支持体外肾小球的吻合和再灌流。微流体技术是突出的特点，因为我相信定义肾单位结构的空间关系的能力将是 将来有必要对灌流的肾小球进行管状引流。]职业发展计划的主要组成部分包括：1)由所述研究战略推动的实验室研究；2)来自具有血管生物学、组织工程、肾脏病和微流体学专业知识的多学科小组的指导；3)参与科学研究 会议；4)数学、微流体学和组织工程主题的正式教学；以及5)负责任地进行研究的监督手稿和拨款提交和指导。这一职业发展计划将在耶鲁大学进行，这是一个出色的环境，保持着一个开放的、支持性的社区，拥有最先进的设施和对成功完成这项申请至关重要的世界级研究人员的汇聚。

 DESCRIPTION (provided by applicant): This K08 mentored career development application describes my four-year plan to complete my training as a physician scientist, combining practice in academic nephrology with an extramurally funded research program relevant to renal disease. More specifically, I propose to develop a research project and the skills necessary to become an independent investigator working in the field of kidney tissue engineering. Having completed an MD-PhD degree from NYU and internal medicine residency and nephrology fellowship at Yale, I maintain a strong desire to do research that impacts clinical problems. I am currently an Instructor in the Department of Internal Medicine at Yale. This K08 award would support the following goals: 1) to conduct renal tissue engineering research; 2) to develop expertise in tissue engineering and microfluidics; and 3) to develop an independent research career. End stage renal disease is a significant and costly problem best treated by kidney transplantation. However, there is a severe shortage of donor organs that could potentially be alleviated by tissue engineered kidney tissue. The functional unit of the kidney is called the nephron which has three primary components: 1) a blood supply 2) a filtration unit called a glomerulus and 3) a tubule to process the filtrate prior to excretion. Preliminary results demonstrated that implantation of endothelial cells with isolated renal glomeruli in vivo led to anastomoses and perfusion of microvessels and glomeruli. [The research proposed here seeks to further understand these anastomoses to significantly advance this renal tissue engineering strategy. Aim 1 is to investigate how glomeruli promote endothelial cell-glomerular anastomoses in vitro and in vivo. Knowledge derived from these studies may significantly improve the efficiency of anastomoses and ultimately glomerular survival and function. Aim 2 is to design a perfusable microfluidics device that supports the anastomoses and re-perfusion of glomeruli through microvascular networks in vitro. Microfluidics technology is featured prominently because I believe the ability to define the spatial relationships of the nephron structures will be necessary to incorporate tubular drainage of the perfused glomeruli in the future.] Key components of the career development plan include: 1) laboratory research driven by the research strategy described; 2) mentorship from a multidisciplinary group with expertise in vascular biology, tissue engineering, nephrology, and microfluidics; 3) participation in scientific conferences; 4) formal didactics in mathematics, microfluidics, and tissue engineering topics; and 5) supervised manuscript and grant submissions and instruction in responsible conduct of research. This career development plan will be carried out at Yale University, an outstanding environment that maintains an open, supportive community with state of the art facilities and a confluence of world-class researchers critical to the successful completion of this application.