Dynamic limits on contraction of gastrointestinal smooth muscle

胃肠平滑肌收缩的动态限制

• 批准号: 8234549
• 负责人: MARION Joyce SIEGMAN
• 金额: $ 31.55万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234549
• 关键词: Accounting; Actins; Asses; Behavior; Bladder neck obstruction; Calcium; Cells; Colon; Confocal Microscopy; Congenital Megacolon; Connective Tissue; Contractile Proteins; Cytoskeleton; Dependence; Diabetes Mellitus; Disease; Distal; Elements; Event; Extracellular Matrix; Failure; Filament; Gastrointestinal tract structure; Genitourinary system; Goals; Growth; Hyperplasia; Hypertrophy; Intestinal Diseases; Intestinal Obstruction; Isometric Exercise; Length; Link; Maintenance; Mechanics; Megacolon; Microfilaments; Modeling; Mus; Muscle; Muscle Cells; Muscle function; Myosin ATPase; Organ; Oryctolagus cuniculus; Output; Physiological; Process; Production; Property; Rattus; Relaxation; Resistance; Rest; Smooth Muscle; Smooth Muscle Myocytes; Spottings; Streptozocin; Structure; Taenia Coli; Testing; Therapeutic Intervention; Time; Tissues; Transmission Electron Microscopy; Vascular Diseases; Work; depolymerization; diabetic; diabetic rat; expectation; extracellular; gastrointestinal; motility disorder; muscle form; polymerization; response; transmission process

DESCRIPTION (provided by applicant): A hallmark of smooth muscle behavior is its ability to adapt to changes in functional demand by remodeling, as in diabetes and in obstructive disorders of the gastrointestinal tract such as megacolon of Hirschsprung's disease, which are a major focus of this project. Remodeling may include smooth muscle growth (hypertrophy, hyperplasia) together with or without concomitant changes in extracellular matrix. Smooth muscle shortening depends on (a) external applied loads and (b) internal resistances provided by the extracellular connective tissue matrix which links smooth muscle cells together and to neighboring cells that are exerting force. Both factors also govern the length-force relationships and shortening range, which may be differentially changed as a result of remodeling. Complicating this further is the recent finding that stimulation initiates a length- dependent polymerization of actin filaments in the cellular cortex, ostensibly strengthening the cytoskeleton and enhancing force, which would be expected to provide an internal load and impede shortening. A rigorous analysis of the effects of the cytoskeletal remodeling on the mechanical properties of intact muscle is warranted. Our structural studies on g.i. smooth muscles prompted our central hypothesis that in intact muscles, overall force output and shortening are limited due to the failure of transmission of events occurring at the crossbridge, resulting from floppiness of the extracellular matrix, contractile filament misalignment and possibly also formation of a stiff cytoskeleton. There is a critical need for an integrated view on how structure limits function in smooth muscle. We will study (1) remodeling in the colon of (a) the lethal spotted murine model of Hirschsprung's megacolon which shows enhanced force production at short muscle lengths and increased compliance, favoring extensive shortening, (b) a rat model of diabetes (streptozotocin), which shows stiffening at rest, enhanced force production at short muscle lengths, and a limited capacity to shorten, and (2) two normal gastrointestinal smooth muscles representing the extremes in their relationships between length and force production and ability to shorten: the rabbit taenia coli and rat anococcygeus m. Our long term goal is to define the mechanisms, physiological and structural, limiting force output and shortening in smooth muscles and, thereby, identify likely candidates for therapeutic intervention following remodeling in disease. Specific Aim 1 is to determine how the extent of actin-myosin interaction and transmission of mechanical events through intra- and extracellular matrices, concomitantly with changes in structural orientation, govern force output of smooth muscle as a function of muscle length. Specific Aim 2 is to determine the mechanical factors that control the polymerization and depolymerization of cytoskeletal actin, and how these dynamic transitions limit force production, shortening and work production in intact muscles. Specific Aim 3 is to define and quantify the composition of the extracellular matrix that account for the drastic and disparate changes in resting compliance that occur following remodeling in the diabetic colon and in the Hirschsprung's megacolon. PUBLIC HEALTH RELEVANCE: Smooth muscles form the walls of organs having conduit and reservoir function. The biomedical significance of this work is derived from the involvement of smooth muscle in motility disorders of the gastrointestinal and urogenital tracts as well as in vascular diseases. In conditions such as diabetes, intestinal and bladder obstruction, adaptations to changes in functional demand occur which include remodeling of muscle cells as well as the connective tissue with which it interacts. The details of cell-cell mechanical interaction in terms of structure and function is relevant to understanding how structural alterations ultimately limit function in these tissues in normal and disease states.

描述（由申请人提供）：平滑肌行为的标志是它能够通过重塑，如糖尿病和胃肠道的阻塞性疾病（例如Hirschsprung氏病的Megacolon）来适应功能需求的变化，这是该项目的主要重点。重塑可能包括平滑肌肉生长（肥大，增生），有或没有伴随细胞外基质的变化。平滑肌缩短取决于（a）外部施加的载荷和（b）细胞外结缔组织基质提供的内部电阻，该基质将平滑肌细胞连接在一起，并与施加力的邻近细胞联系起来。这两个因素还控制着长度的关系和缩短范围，这可能会因重塑而差异化。最近的发现是，刺激会引发细胞皮质中肌动蛋白丝的长度依赖性聚合，表面上可以增强细胞骨架并增强力，这将有望提供内部载荷并妨碍缩短。有必要对细胞骨架重塑对完整肌肉机械性能的影响进行严格分析。我们关于G.I.的结构研究平滑的肌肉促使我们的中心假设，即由于细胞外矩阵的平淡无奇，收缩细丝不对对准以及可能形成僵硬的细胞骨架，在完整的肌肉中，整体力量输出和缩短受到限制。关于结构限制如何在平滑肌中运作的综合视图迫切需要。 We will study (1) remodeling in the colon of (a) the lethal spotted murine model of Hirschsprung's megacolon which shows enhanced force production at short muscle lengths and increased compliance, favoring extensive shortening, (b) a rat model of diabetes (streptozotocin), which shows stiffening at rest, enhanced force production at short muscle lengths, and a limited capacity to shorten, and (2) two normal胃肠道平滑肌肉代表其长度和力产生之间关系的极端以及缩短的能力：兔子taenia大肠杆菌和大鼠的无卵球菌。我们的长期目标是定义平滑肌肉的机制，生理和结构性，限制力输出和缩短，从而确定疾病重塑后可能进行治疗干预的候选者。具体目的1是确定肌动蛋白膜肌球蛋白相互作用的程度以及通过细胞内和细胞外矩阵传播机械事件的程度，并与结构取向的变化同时控制平滑肌的力量作为肌肉长度的函数。具体目的2是确定控制细胞骨骼肌动蛋白聚合和解聚的机械因素，以及这些动态转变如何限制完整肌肉中的力产生，缩短和工作产生。具体目的3是定义和量化细胞外基质的组成，这些基质解释了糖尿病结肠和赫希斯普朗的巨型巨龙的重塑后发生的静止依从性的急剧变化。 公共卫生相关性：光滑的肌肉形成具有导管和储层功能的器官的墙壁。这项工作的生物医学意义来自平滑肌参与胃肠道和泌尿生殖道的运动障碍以及血管疾病。在糖尿病，肠道和膀胱阻塞等条件下，适应功能需求变化的适应，包括对肌肉细胞的重塑以及与之相互作用的结缔组织。在结构和功能方面，细胞细胞机械相互作用的细节与了解结构变化最终如何限制正常和疾病状态中这些组织中的功能。