项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

MULLINS, CHRISTOPHER V.

项目受资助机构

UNIVERSITY OF SOUTHERN CALIFORNIA

项目编号

5R01DK064324-15

立项年度

2019

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

432737.00美元

学科

Kidney Disease; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

PETI-PETERDI, JANOS

参与机构

NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

项目标书摘要：? DESCRIPTION (provided by applicant): This study aims to explore a new mechanism of kidney regeneration which is based on newly identified angiogenic and glomerulotrophic functions of macula densa (MD) cells, and to test its potential therapeutic utility in chronic kidny disease (CKD). Our overall, long-term vision is that a new therapeutic approach, fundamentally different from existing strategies, one that amplifies this novel intrinsic renal repair mechanism, will provide the ultimate cure for this devastating disease. The salt-sensing macula densa (MD) cells of the distal tubule are chief cells within the kidney, strategically positioned at the glomerular entrance, and play key sensory and regulatory functions in body fluid- electrolyte homeostasis. Preliminary work using intravital multiphoton microscopy (MPM) of the same intact kidney region over several days provided visual clues that in response to MD-derived signals, mesenchymal progenitor cells residing in the renal interstitium proliferate and migrate towards the MD, and via the vascular pole into the glomerulus and proximal tubules. Therefore we hypothesize that MD cells are master regulators of renal tissue remodeling, and perform this new, non-traditional function via the generation of novel secreted angiogenic and glomerulotrophic factors, and their paracrine actions on the reactivation and recruitment of mesenchymal progenitor cells. Further, we hypothesize that augmenting these MD mechanisms in CKD may result in rapid tissue remodeling and improved kidney structure and function (regression). This project will use comprehensive experimental approaches including new transgenic mouse models, cell fate tracking, MD transcriptome analysis, bioinformatics, MPM imaging, and a model of focal segmental glomerulosclerosis (FSGS). The specific aims are to (1) functionally characterize the novel renal tissue remodeling function of MD cells, and to (2) examine the effects of MD activation on kidney structure and function in CKD. These novel MD cell functions may be targeted in the future development of new therapeutic approaches for the better treatment of CKD.