权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

From human keratinocytes to biological pacemakers

从人类角质形成细胞到生物起搏器

基本信息

批准号：
8423701
负责人：
IRA S COHEN
金额：
$ 63.59万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423701
关键词：
Action Potentials Adult American Animal Experiments Anterior Antigens Autologous Automobile Driving Biochemical Biological Biological Pacemakers Calcium Canis familiaris Cardiac Cardiac Myocytes Cell Lineage Cells Characteristics Clinical Complement Connexins Coupling Development Disease Dreams Effectiveness Excision Exhibits Fibroblasts Future Gap Junctions Gene Chips Gene Expression Gene Expression Profile Genetic Giant Cells Goals Hair follicle structure Health Benefit Heart Heart Atrium Heart Block Human Immunohistochemistry Immunosuppression Implant In Vitro Individual Injection of therapeutic agent Ion Channel Israel Label Left Location Mechanics Membrane Methods Microelectrodes Molecular Molecular Profiling Monitor Morphology Muscle Cells Pacemakers Patients Physiological Population Property Protocols documentation Quality of life Research Reverse Transcriptase Polymerase Chain Reaction Sinus Site Source Staining method Stains Techniques Testing Therapeutic United States Universities Ventricular Western Blotting base cell type connexin 40 electronic pacemaker heart cell heart rate variability heart rhythm human GJB2 protein implantation in vivo induced pluripotent stem cell keratinocyte nodal myocyte novel novel strategies patch clamp performance site repaired research study response stem cell biology

项目摘要

Project Summary: The long term goal of this application is to create a pure population of cardiac pacemaker cells from an easily accessible autologous cell type, the human hair follicle keratinocyte (HFKT-pacemakers), to characterize their pacemaker mechanism, their ability to integrate into the cardiac syncytium and their potential to function as an in vivo biological pacemaker. If successful in the long term, the health benefit of such an approach will be to substitute for the more than 350,000 electronic pacemakers implanted or reimplanted in patients in the United States each year. The project has four specific aims: (1) to expand the population of induced pluripotent stem cells created from the HFKTs, enhance their differentiation to a cardiac lineage and select for pacemaker myocytes; (2) to characterize the membrane currents in the HFKT- pacemakers as well as their pacemaker function and gene expression profile, and to compare the HFKT- pacemaker to native cardiac primary and secondary pacemakers in vitro; (3) to determine (a) the ability of HFKT pacemakers to couple to adult heart cells from specific locations (atrium or ventricle) in vitro and whether the pacing rate generated is target dependent (b) which connexins HFKT-pacemakers express and the ability of the HFKT-pacemakers to couple to cells expressing fibroblast connexins (a potentially arrhythmogenic situation); (4) to determine in vivo biological pacemaker function generated by placement of HFKT-pacemakers in the canine atrium or ventricle. Our approach will employ 1) novel methods to enhance selection of pacemaker cells, 2) patch clamping to characterize action potential morphology and membrane currents in the isolated pacemaker cells generated, 3) gene chips to determine the pacemaker cells' expression profile, 4) dual whole cell patch clamp, and biochemical and molecular techniques to determine connexin expression and functional cell to cell coupling 5) Injection of the HFKT- pacemakers into the canine atrium or ventricle to determine in vivo pacemaker function. The experiments will be carried out by a team of long term collaborators at Stony Brook University and at the Technion in Israel. The team has extensive expertise in stem cell biology, induced pluripotent stem cells, cardiac pacemaking, patch clamp,, and in vivo studies of biological pacemaker function. Successful execution of the research plan will enhance selection techniques for cardiac cell lineages from IPSCs, characterize the basis of pacemaker activity in the HFKT- pacemakers and determine their effectiveness as an in vivo biological pacemaker. If the HFKT-pacemaker functions well in the canine heart, a future goal would be to advance this novel autologous, cellular approach towards clinical deployment.

项目概述：本应用程序的长期目标是创建一个纯人口的心脏起搏器