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Pacemaker cells and mechanism in the renal pelvis

肾盂起搏细胞及其机制

基本信息

批准号：
10116375
负责人：
KENTON M SANDERS
金额：
$ 47.77万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116375
关键词：
Address Affect Alpha Cell Anatomy Animal Model Automobile Driving Biological Markers Bladder Cells Chimeric Proteins Data Defect Development Diabetes Mellitus Distal Electrophysiology (science)Exhibits Fertilization Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Profiling Generations Heart Histones Hydronephrosis Image In Situ Inflammation Intervention Investigation Ion Channel Kidney Kidney Failure Location Molecular Monitor Morphology Mouse Strains Mus Muscle Obstruction Organ Outcome Study PDGFRB gene Pacemakers Pathologic Periodicity Peristalsis Phenotype Physiological Platelet-Derived Growth Factor alpha Receptor Population Population Heterogeneity Pump Reagent Regulatory Pathway Renal pelvis Reporter Role Signal Pathway Signal Transduction Signaling Molecule Site Smooth Muscle Smooth Muscle Myocytes Techniques Testing Therapeutic Intervention Tissue Model Tissues Transgenic Mice Ureter Urinary tract Urine Visceral cell type clinical investigation follow-up interstitial interstitial cell kidney cell new technology nodal myocyte novel optogenetics pre-clinical preclinical study prevent promoter receptor renal damage sensor targeted treatment therapeutic evaluation

项目摘要

Project Summary The renal pelvis (RP), a smooth muscle organ that transports urine from the kidney to the ureter, generates regular rhythmic contractions that are vital for urine transport and bladder filling. Propagating contractions originate in the most proximal region of the RP, where specialized cells, called “atypical” smooth muscle cells (ASMCs)”, have been proposed to serve as the pacemaker cells. However, identification of ASMCs has been imprecise, and thus experimental findings regarding their phenotype and functions are controversial. Ambiguities arise from the lack of specific markers for ASMCs and have prevented understanding the role of ASMC in driving peristaltic contractions or the mechanism of pacemaker activity in the RP. Newer technologies can now identify specific cell-types within tissues composed of heterogeneous populations of cells. This study will employ strains of mice with cell-specific reporters and optogenetic sensors to clarify how the pacemaker and responder cells of the RP generate peristaltic contractions. Our preliminary data show that the specialized cells, ASMCs, express platelet-derived-growth-factor-receptor-alpha (PDGFRα), and using transgenic mice that express a histone 2B- eGFP fusion protein driven off the endogenous PDGFRα+ promoter, we can identify these cells unequivocally in intact tissues or in enzymatic dispersions of the tissues. We hypothesize that PDGFRα+ cells are pacemaker cells in the renal pelvis. The following Specific Aims will be addressed: 1. Test the hypothesis that PDGFRα+ are the primary pacemaker cells of the RP; 2. Investigate the dynamics of Ca2+ signaling in PDGFRα+ cells; 3. Elucidate the specific mechanisms of pacemaker generation and propagation. Because of their specialized function as pacemaker cells, PDGFRα+ cells are likely to have specialized gene expression patterns that encode essential ionic conductances and other signaling molecules to facilitate pacemaker activity. This will be investigated by analysis of gene expression in FACS-enriched populations PDGFRα+ cells isolated from the proximal RP of the reporter strain of mice. Mice expressing a genetically encoded Ca2+ indicator (GECI) in PDGFRα + cells will be used to image Ca2+ signaling in PDGFRα+cells in situ. The ion channels activated by Ca2+ dynamics will be determined and the consequences of this conductance in RP peristalsis will be evaluated. Preliminary data show that PDGFRα+ cells exhibit dynamic Ca2+ signaling in situ and express the Ca2+-activated- Cl- channel, Ano1, making this a prime candidate for the pacemaker conductance. This project will serve as a basis for future studies to understand developmental or pathological problems affecting RP function. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

项目总结