Arterial Medial Calcification and Cell Differentiation

动脉中层钙化和细胞分化

基本信息

批准号：
7261506
负责人：
Yanfeng Speer
金额：
$ 9.82万
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/7261506
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 Transgenic Organisms Translational Research Universities Vascular calcification Washington calcification calcium phosphate career diabetic gene repression inorganic phosphate mortality mouse Smc1l1 protein mouse Smc1l2 protein 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）：该提案的主要目标是培训首席研究员并使其成为心血管病理学领域的独立科学家，重点研究慢性肾脏病（CKD）和糖尿病。具体来说，该计划提出了详细的职业发展计划和研究计划，涉及血管细胞分化的机制研究和血管中层钙化的表型调节，这种现象已在终末期肾病和糖尿病患者中观察到。职业发展计划包括指导、课程作业、研究培训、与科学界的互动以及领导和管理技能的发展。这将促进主要研究者在与 CKD 和糖尿病相关的心血管病理学转化研究领域的科学发展。血管内侧钙化在 CKD 和 II 型糖尿病患者中发生频率较高，被推荐作为该人群心血管死亡率以及冠心病、中风和小羊截肢未来事件的强有力的独立预测因子。在初步实验中，主要研究者发现血管壁细胞似乎在介导血管钙化中发挥着至关重要的作用，在血管钙化中观察到软骨化生和骨软骨组织。了解钙化病变中参与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，以预防和潜在逆转与 CKD 和糖尿病相关的血管钙化。为了实现这一目标，主要研究者提出了以下三个具体目标：1）利用尿毒症和转基因小鼠模型确定动脉中层钙化中观察到的骨软骨形成细胞的起源； 2）确定磷酸盐和钙在体外血管SMC表型转变中的作用以及钙化动脉介质中骨软骨形成细胞的基因表达谱； 3)确定血管钙化过程中SMC谱系下调和Erk1/2活性的要求和机制。华盛顿大学为拟议的研究和转化科学家的发展提供了良好的环境。在本奖项的前瞻性支持下，这种环境将使首席研究员能够获得技术和批判性思维技能，从而作为一名独立科学家获得成功的职业生涯。