Dynamic limits on contraction of gastrointestinal smooth muscle

胃肠平滑肌收缩的动态限制

• 批准号: 8330804
• 负责人: MARION Joyce SIEGMAN
• 金额: $ 31.78万
• 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/8330804
• 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.

描述（由申请人提供）：平滑肌行为的一个标志是其通过重塑适应功能需求变化的能力，如糖尿病和胃肠道梗阻性疾病，如先天性巨结肠，这是本项目的主要重点。重塑可能包括平滑肌生长（肥大、增生），伴随或不伴随细胞外基质的变化。平滑肌缩短取决于（a）外部施加的负荷和（B）由细胞外结缔组织基质提供的内部阻力，所述细胞外结缔组织基质将平滑肌细胞连接在一起并连接到施加力的相邻细胞。这两个因素也决定了长度-力关系和缩短范围，这可能会因重塑而发生差异性变化。使这一问题进一步复杂化的是，最近发现刺激会引发细胞皮质中肌动蛋白丝的长度依赖性聚合，表面上增强了细胞骨架并增强了力，预计这将提供内部负载并阻止缩短。细胞骨架重塑对完整肌肉力学性能的影响的严格分析是必要的。我们对胃肠的结构研究。平滑肌提示了我们的中心假设，即在完整的肌肉中，由于细胞外基质的松弛、收缩丝的错位以及可能形成的僵硬的细胞骨架导致在横桥处发生的事件的传递失败，总的力输出和缩短受到限制。有一个关键需要一个综合的观点如何结构限制平滑肌功能。我们将研究（1）（a）先天性巨结肠的致死斑点鼠模型的结肠重塑，其显示在短肌肉长度下的增强的力产生和增加的顺应性，有利于广泛的缩短，（B）糖尿病大鼠模型（链脲佐菌素），其显示静止时的僵硬，在短肌肉长度下增强的力量产生，以及有限的缩短能力，和（2）两个正常的胃肠平滑肌，代表了它们在长度和力的产生以及缩短能力之间的极端关系：兔结肠带和大鼠肛尾肌M。我们的长期目标是确定机制，生理和结构，限制力输出和缩短平滑肌，从而确定可能的候选人进行治疗干预后重塑疾病。具体目标1是确定肌动蛋白-肌球蛋白相互作用的程度和通过细胞内和细胞外基质的机械事件的传输，伴随着结构方向的变化，作为肌肉长度的函数来控制平滑肌的力输出。具体目标2是确定控制细胞骨架肌动蛋白的聚合和解聚的机械因素，以及这些动态转换如何限制完整肌肉的力产生，缩短和做功。具体目标3是定义和量化细胞外基质的组成，其解释了糖尿病结肠和先天性巨结肠重塑后发生的静息顺应性的剧烈和不同的变化。