Molecular Analysis of Scarless Fetal Wound Healing

描述（由申请人提供）：成年哺乳动物组织对损伤的反应是愈合并形成疤痕。疤痕组织有助于密封伤口，但也可能导致严重的发病率。瘢痕可限制肌腱和肌肉运动，阻塞内脏腔，阻碍周围神经再生。尤其是在头部和颈部，疤痕会产生严重的后果，导致听力丧失、嗅觉和味觉丧失、声音和发音丧失、气道阻塞，以及明显的明显可见的畸形。与成人相比，哺乳动物胎儿在类似再生的过程中愈合无疤痕。这种非凡的能力被认为是胎儿组织固有的，独立于子宫环境，并在妊娠晚期失去。了解无疤痕愈合的生物学基础可能会导致新的策略来限制疤痕的发病率。我们假设无疤痕的胎儿伤口愈合驱动来自胎儿与成人差异表达的基因子集。该项目的目标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，识别差异调节基因，更好地表征选择的差异调节基因产物，并通过蛋白质组学方法确认蛋白质水平上的差异表达。我们将评估有希望的候选基因，从而确定其在许多模型系统中的生物学意义，包括转基因和敲除动物，并通过使用体细胞基因转移。我们还将研究控制胎儿伤口特异性伴侣蛋白亚基下调的可能机制。通过这些互补的方法，我们希望对控制胎儿和成人伤口愈合的基因模式有一个广泛的了解，并确定对两者都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.