Investigating endothelial cell and glomerular anastomoses to advance kidney tissue engineering

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 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.