Regulatory Mechanisms in Lymphatic Muscle Contraction

淋巴肌收缩的调节机制

基本信息

批准号：
8105099
负责人：
MARIAPPAN MUTHUCHAMY
金额：
$ 10.04万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
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：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105099
关键词：
Actins Address Adrenergic Agonists Affect Animals Bathing Behavior Binding Blood Circulation Body Fluids Body Regions Bradykinin Buffers Calcium Caliber Cardiac Cardiovascular system Cells Central Vein Characteristics Chest Clinical Complement Contractile Proteins Data Depressed mood Disease Down-Regulation Edema Equilibrium Exhibits Functional disorder Gene Expression Gene Knock-Out Model Generations Genes Genomics Goals Immune Immunoblotting Immunofluorescence Immunologic Immunoprecipitation Inflammation Mediators Injury Isometric Contraction Japan Knock-out Knockout Mice Laboratories Levosimendan Lymph Lymphatic Lymphatic System Lymphatic vessel Lymphocyte Measurement Measures Mediating Mesentery Methods Microfilaments Molecular Molecular Genetics Molecular Profiling Monitor Motor Mus Muscle Muscle Contraction Muscle Proteins Muscle function Myosin Heavy Chains Myosin Light Chain Kinase Myosin Light Chains Nature Peptides Pharmaceutical Preparations Phosphorylation Physiological Play Preparation Protein Isoforms Proteins Proteomics RNA Rattus Regulation Regulatory Element Regulatory Pathway Research Research Project Grants Role Saline Series Signal Pathway Skin Small Interfering RNA Smooth Muscle Smooth Muscle Myosins Striated Muscles Students Substance P System Temperature Testing Thick Filament Thin Filament Thoracic Duct Tissues Training Transducers Transfection Transgenic Mice Transgenic Model Tropomyosin Troponin Troponin C Tungsten United States National Institutes of Health Vascular Smooth Muscle Visit Western Blotting abstracting base caldesmon calponin career genetic regulatory protein immune function kinase inhibitor knock-down knowledge base lipid metabolism lymph flow mRNA Expression mouse model neoplastic cell non-muscle myosin heavy chain-B overexpression pressure promoter research study response synthetic peptide therapy development tool

项目摘要

DESCRIPTION (provided by applicant): My immediate career objectives are to develop a reputation for high quality research and to train graduate and postdoctoral students in the cardiovascular and lymphatic research field. My long-term career are to advance the level of understanding the regulatory mechanisms of lymphatic muscle contractility under normal and diseased/pathophysiological conditions. Lymphatic muscle exhibits strong/phasic contractions, much higher shortening velocities and different intracellular calcium dynamics. Unfortunately little information is known about the molecular mechanisms that are responsible for these unique characteristics. In this proposal we will use the available contractile protein gene knock out models or transgenic models with overexpression of contractile protein isoforms to test the central hypothesis remodeling of thick or thin filament proteins in the contractile apparatus of lymphatic muscle modulates its contractile dynamics through altering the calcium sensitivity and crossbridge activation mechanisms. The specific aims are: (1) To determine the functional roles of SM-B myosin heavy chain (MHC) in the phasic and tonic contraction of lymphatics, (2) To define the roles of tropomyosin in the thin filament-mediated contraction of lymphatics. We will use SM-B MHC knockout and SM-MHC/calponin double knockout mouse models. The vascular smooth muscle a-actin promoter will be to express striated muscle tropomyosin in lymphatic muscle. An adenoviral siRNA approach will be used knock down the smooth muscle a- and p-TM gene expression in lymphatics. We will isolated/cannulated vessels from iliac and thoracic duct lymphatics to study the contractile characteristics of lymphatics. Force and calcium measurements will be conducted in the lymphatic segment preparations (both intact and skinned) to determine the calcium sensitivity and cooperativity mechanisms of lymphatics. The contractile mechanisms of lymphatics are poorly understood and this study will significantly advance our knowledge of the basis for the lymphatic vessel function. These studies further advance my training lymphatic research using mouse models, which would allow me to develop and use genomic proteomic approaches to determine the signaling pathways that regulate lymphatic muscle function. (End of Abstract)

描述（由申请人提供）：我的近期职业目标是建立高质量研究的声誉，并培训心血管和淋巴研究领域的研究生和博士后。我的长期职业是提高对正常和患病/病理生理条件下淋巴肌收缩力调节机制的理解水平。淋巴肌表现出强烈/阶段性收缩、更高的缩短速度和不同的细胞内钙动力学。不幸的是，我们对造成这些独特特征的分子机制知之甚少。在本提案中，我们将使用现有的收缩蛋白基因敲除模型或过度表达收缩蛋白亚型的转基因模型来测试中心假设：淋巴肌收缩装置中粗丝或细丝蛋白的重塑通过改变钙来调节其收缩动力学。敏感性和跨桥激活机制。具体目标是：(1) 确定 SM-B 肌球蛋白重链 (MHC) 在淋巴管的阶段性和强直性收缩中的功能作用，(2) 确定原肌球蛋白在细丝介导的淋巴管收缩中的作用。我们将使用 SM-B MHC 敲除和 SM-MHC/calponin 双敲除小鼠模型。血管平滑肌α-肌动蛋白启动子将在淋巴肌中表达横纹肌原肌球蛋白。腺病毒 siRNA 方法将用于降低淋巴管中平滑肌 a- 和 p-TM 基因的表达。我们将从髂管和胸导管淋巴管中分离/插管血管，以研究淋巴管的收缩特征。将在淋巴段制剂（完整的和带皮的）中进行力和钙测量，以确定淋巴管的钙敏感性和协作机制。人们对淋巴管的收缩机制知之甚少，这项研究将显着增进我们对淋巴管功能基础的了解。这些研究进一步推进了我使用小鼠模型进行的淋巴训练研究，这将使我能够开发和使用基因组蛋白质组学方法来确定调节淋巴肌功能的信号通路。（摘要完）