Role of FACIT Collagens in Hypertension

描述 (申请人摘要)肺动脉高压可以是主要事件， 或继发于其他伤害。无论是哪种情况，它都是一个重要的临床 损伤血管的管壁迅速增厚的问题。部分 这种快速增厚是由细胞外的从头合成引起的。 帮助定义心脏的医疗层和外膜层的矩阵组件 血管。这种增厚反过来会导致管腔减少。 直径，增加血流阻力，并最终提高动脉 压力。在动物身上，如果疾病没有发生，这种损害是可逆的。 如果排除了根本原因，就会出现这种情况。这种高血压 回归已经在动物模型中得到了很好的记录，但鲜为人知 关于血管重塑的正常机制。在……里面 特别是低氧性肺动脉高压的大鼠模型经常被使用。 因为它具有人类疾病的许多共同特征。 胶原蛋白在成熟的功能性组织的发育中起着重要的作用。 结缔组织的细胞外基质部分由 异型胶原纤维。在超微结构上，各种结缔组织 然而，具有不同的胶原纤维排列和排列， 尽管出现了纤维，但在心脏中发现的胶原蛋白类型 纤维通常是相同的，它们的空间排列由 与纤维或原纤束表面相关的分子， 建立和/或稳定各种空间安排。这样的分子 将至少包含两个域：一个域锚定 分子到纤维表面和第二结构域，以协助各种 与其他纤维或其他基质成分的相互作用。蛋白质与 这些特征包括被分类的胶原蛋白IX、XII和XIV 作为原纤维伴生的胶原蛋白，具有中断的三螺旋(FAITS)。的 这类分子，胶原蛋白XII和XIV存在于各种 含有I型胶原并位于I型胶原表面的组织 纤维的容量未知。我们假设XII型和XIV型 胶原蛋白被用来暂时稳定纤维之间的相互作用 应激状态，如缺氧。这种纤维的稳定将使 组织结构能够承受快速增加所产生的力 胶原纤维含量高，细胞增殖快。我们也 假设XII和XIV型胶原蛋白与 血管壁的可逆性改变。这些分子很容易被除去。 从原纤维表面，允许更永久的稳定剂取代它们的位置 (如原纤维融合或裂解交联)，这是原纤维的适应性， 使血管改变成为永久性的。我们建议研究这些因素的作用 胶原蛋白在高血压大鼠模型中的应用 分子生物学技术。

DESCRIPTION (Applicant's abstract) Pulmonary hypertension may be either a primary event, or secondary to other injury. In either case it is an important clinical problem in which the walls of injured blood vessels rapidly thicken. Part of this rapid thickening is caused by the de novo synthesis of the extracellular matrix components that help define the medical and adventitial layers of the blood vessels. This thickening in turn can result in decreased lumen diameter, increasing resistance to blood flow and ultimately raising arterial pressure. In animals, the damage is reversible if the disease has not progressed and if the underlying cause is removed. This hypertension regression has been well documented in animal models, but little is known about the normal mechanisms regarding this remodeling of the vessels. In particular, the rat model of hypoxic pulmonary hypertension is frequently used as it has in common many of the features of the human disease. Collagens play a major role in the development of mature, functional tissues. The extracellular matrix of connective tissue is composed, in part, of heterotypic collagen fibrils. Ultrastructurally, various connective tissue have different collagen fibrillar arrangements and alignments, however, despite the appearance of the fibrils, the types of collagens found in the fibrils are frequently the same, their spatial arrangements determined by molecules associated with the surfaces of fibrils or fibril bundles that establish and/or stabilize the various spatial arrangements. Such molecules would be expected to contain at least two domains: One domain that anchors the molecule to the surface of the fibril and a second domain to assist in various interactions with other fibrils or other matrix components. Proteins with such characteristics include collagens IX, XII, and XIV, which are classified as Fibril Associated Collagens with Interrupted Triple-helices (FACITs). Of this class of molecules, collagens XII and XIV are found in a variety of tissues that contain type I collagen and sit on the surface of the collagen I fibrils in an unknown capacity. We hypothesize that types XII and XIV collagen are recruited to temporarily stabilize fibril interactions under conditions of stress, such as hypoxia. This fibril stabilization would allow the tissue architecture to withstand the forces generated by a rapid increase in fibrillar collagen content and rapid cell proliferation. We also hypothesize that the types XII and XIV collagen are responsible for the reversibility of the vessel wall changes. These molecules are easily removed from fibril surfaces, allowing more permanent stabilizers to take their places (such as fibril fusion or lysly crosslinking), which are fibril adaptions that make the vessel changes permanent. We propose to examine the role of these collagens in the hypertensive rat model using a variety of biochemical and molecular biological techniques.