Molecular Analysis of Scarless Fetal Wound Healing

描述(申请人提供)：成年哺乳动物组织对损伤的反应是愈合并形成疤痕。疤痕组织有助于封闭伤口，但也可能导致严重的发病率。瘢痕可以限制肌腱和肌肉的运动，阻塞内脏腔，阻碍周围神经再生。头部和颈部的疤痕尤其严重，会导致听力丧失、嗅觉和味觉丧失、声音和发音丧失、呼吸道阻塞，以及明显的肉眼可见畸形的污名。与成人不同的是，哺乳动物胎儿在类似于再生的过程中愈合时没有疤痕。这种非凡的能力已知是胎儿组织固有的，与子宫环境无关，并在妊娠晚期消失。对无疤痕愈合的生物学基础的了解很可能导致限制瘢痕发病率的新策略。我们假设，无疤痕胎儿伤口愈合是由胎儿与成人差异表达基因的子集驱动的。该项目的目的是建立包含完整相关基因集的微阵列，包括愈合胎儿和成人伤口的表达体系，识别差异调控基因，更好地表征选定的差异调控基因产物，并通过蛋白质组学方法在蛋白质水平上确认差异表达。我们将评估这样确定的候选基因在一些模型系统中的生物学意义，包括转基因和基因敲除动物，并通过使用体细胞基因转移。我们还将研究控制胎儿创伤特异性ETA伴侣蛋白亚单位下调的可能机制。通过这些互补的方法，我们希望借此对控制胎儿和成人伤口愈合的基因模式达成广泛的理解，并确定对两者至关重要的基因产物/途径。

DESCRIPTION (provided by applicant): Adult mammalian tissues respond to injury by healing with scar formation. Scar tissue assists in sealing a wound, but can also lead to significant morbidity. Scar can restrict tendon and muscle movement, obstruct visceral lumens, and impede peripheral nerve regeneration. In the head and neck especially scarring can have severe consequences, causing hearing loss, loss of smell and taste, loss of voice and articulation, airway obstruction, as well as the obvious stigma of gross visible deformity. In contrast to adults, mammalian fetuses are known to heal without scar in a process akin to regeneration. This remarkable ability is known to be intrinsic to fetal tissues, independent of the uterine environment, and is lost in the third trimester of gestation. An understanding of the biological basis for scarless healing might well lead to new strategies to limit the morbidity of scar. We hypothesize that scarless fetal wound healing drives from a subset of differentially expressed genes in fetuses versus adults. The aims of this project are to establish microarrays that encompass the full relevant gene set comprising the expressomes of healing fetal and adult wounds, to identify differentially regulated genes, to better characterize selected differentially regulated gene products, and to confirm differential expression at the protein level through a proteomics approach. We will evaluate promising candidate genes thus identified for their biological significance in a number of model systems, including transgenic and knockout animals, and through the use of somatic gene transfer. We will also investigate possible mechanisms controlling the fetal wound-specific downregulation of the eta chaperonin subunit. With these complementary approaches we hope to thereby arrive at a broad understanding of the gene patterns controlling both fetal and adult wound healing, and identify gene products/pathways critical to both.