Arterial Medial Calcification and Cell Differentiation

动脉中层钙化和细胞分化

基本信息

批准号：
7586700
负责人：
Yanfeng Speer
金额：
$ 11.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586700
关键词：
Amputation Area Arterial Medias Award Blood Vessels Bone Marrow Transplantation Calcified Cardiovascular Pathology Cardiovascular system Cell Differentiation process Cell Wall Cells Chronic Kidney Failure Community Developments Coronary heart disease Development Development Plans Diabetes Mellitus Down-Regulation End stage renal failure Environment Event Frequencies Future Gene Expression Gene Expression Profile Genes Goals In Vitro LacZ Genes Lasers Leadership Lesion Location Medial Mediating Mentorship Metaplasia Microdissection Mus Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus Patients Phosphorylation Play Population Principal Investigator Research Research Personnel Research Training Role Scientist Stroke Thinking Training Transgenic Mice Translational Research Universities Vascular calcification Washington calcification calcium phosphate career career development diabetic patient gene repression inorganic phosphate mortality mouse model myocardin novel therapeutics osteochondral tissue prevent programs prospective research study sevelamer skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this proposal is to train and bridge the principal investigator toward becoming an independent scientist in the field of cardiovascular pathology with a focus on chronic kidney disease (CKD) and diabetes mellitus. Specifically this program proposes a detailed career development plan and a research plan involving mechanistic studies of vascular cell differentiation and phenotypic modulation in vascular medial calcification, a phenomenon that has been observed in ESRD and diabetic patients. The career development plan includes mentorship, coursework, research training, interaction with the scientific community, and development of leadership and management skills. This will enhance scientific development of the principle investigator in a translational research area of cardiovascular pathology associated with CKD and diabetes mellitus. Vascular medial calcification occurs at high frequency in patients with CKD and type II diabetes mellitus, and is recommended as a strong independent predictor of cardiovascular mortality as well as future events of coronary heart disease, stroke, and lower-lamb amputation in this population. In preliminary experiments, the principle investigator has found that vascular wall cells appear to play a crucial role in mediating vascular calcification where cartilaginous metaplasia and osteochondral tissue is observed. Understanding the origins of the cells participating in osteochondral tissue formation in calcified lesions and the mechanisms controlling the cell differentiation may aid in the development of novel therapeutic strategies to prevent and potentially reverse vascular calcification associated with the CKD and diabetes. To fulfill this goal, the principal investigator has proposed the following three specific aims: 1) to determine origins of osteochondrogenic cells observed in arterial medial calcification using uremic and transgenic mouse models; 2) to determine the role of phosphate and calcium in the phenotypic transition of vascular SMCs in vitro and the gene expression profile of osteochondrogenic cells in calcified arterial media; and 3) to determine the requirement and mechanisms of SMC lineage down-regulation and Erk1/2 activity during vascular calcification. The University of Washington represents an outstanding environment for the proposed studies and the development of translational scientists. With the prospective support from the present award, this environment will allow the principal investigator to acquire the technical and critical thinking skills toward a successful career as an independent scientist.

描述（由申请人提供）：该提案的主要目的是训练和桥接主要研究人员，以成为心血管病理领域的独立科学家，重点是慢性肾脏病（CKD）和糖尿病。具体而言，该计划提出了一项详细的职业发展计划和研究计划，其中涉及血管内侧钙化中血管细胞分化和表型调节的机理研究，这是ESRD和糖尿病患者中观察到的现象。职业发展计划包括指导，课程工作，研究培训，与科学界的互动以及领导和管理技能的发展。这将增强与CKD和糖尿病相关的心血管病理的转化研究领域中原理研究者的科学发展。血管内侧钙化发生在CKD和II型糖尿病患者的高频中，并建议作为心血管死亡率的强有力的独立预测指标，以及该人群中冠心病，中风和下lamb截肢的未来事件。在初步实验中，原理研究者发现，血管壁细胞在介导的血管钙化中似乎起着至关重要的作用，在介导软骨化生和骨软骨组织的血管钙化中。了解参与钙化病变中骨软骨组织形成的细胞的起源以及控制细胞分化的机制，可能有助于开发新的治疗策略，以预防与CKD和糖尿病相关的潜在逆转血管钙化。为了实现这一目标，主要研究者提出了以下三个特定目的：1）确定使用尿毒症和转基因小鼠模型在动脉内侧钙化中观察到的骨软骨成生成细胞的起源； 2）确定磷酸盐和钙在体外血管SMC的表型过渡中的作用，以及在钙化动脉培养基中骨软骨细胞的基因表达谱； 3）在血管钙化过程中确定SMC谱系下调和ERK1/2活性的需求和机制。华盛顿大学代表了拟议研究和转化科学家的发展的杰出环境。在当前奖项的前瞻性支持下，该环境将使主要研究人员能够获得技术和批判性思维技能，以成功地成为独立科学家的职业生涯。