The role of HIF-1a in Skin Biology

缺氧诱导因子HIF-1α广泛表达，但经历蛋白酶体降解 在正常氧气条件下。然而，由于皮肤自然缺氧，HIF-1α稳定 免疫组织化学方法检测到其在表皮和毛囊中的表达。我们观察到， HIF-1α缺失的小鼠出生后会出现皮肤病变，其特征是 表皮增厚和脱发。最近的研究表明，HIF-1α调节p21的表达。 角质形成细胞，并与体外培养角质形成细胞的细胞周期停滞相关。这项提案将考验 以下假设：HIF-1α在调节角质形成细胞增殖和 体内分化依赖于c-Myc。为了检验这一假设，我们将(1)确定 HIF-1α在表皮中的表达，以及(2)决定表皮HIF-1α活性的介质，主要集中在c-1-α。 MYC。拟议的实验将使我们能够对HIF-1α在 角质形成细胞。这项研究的总体目标是了解HIF-1α调节的程度 生理环境中的生物过程，如表皮，以及通过它的机制 ACTS，以及这种现象如何在体内平衡和皮肤分化中促进皮肤生长和分化 疾病。

The hypoxia inducible factor HIF-1 alpha is ubiquitously expressed but undergoes proteosomal degradation under normal oxygen conditions. However, because the skin is naturally hypoxic, HIF-1 alpha is stably expressed and detectable by immunohistochemistry in the epidermis and hair follicle. We have observed that mice in which HIF-1 alpha has been deleted postnatally develop skin lesions that are characterized by epidermal thickening and hair loss. Recent research has shown that HIF-1 alpha regulates p21 expression in keratinocytes, and correlates with cell cycle arrest in cultured keratinocytes in vitro. This proposal will test the following hypothesis: HIF-1 alpha plays an essential role in regulating keratinocyte proliferation and differentiation in vivo in a c-Myc dependent manner. To test this hypothesis, we will (1) determine the role of HIF-1 alpha in the epidermis and (2) determine the mediators of epidermal HIF-1 alpha activity, focusing on c- Myc. The proposed experiments will allow us to conduct initial investigations into the role of HIF-1 alpha in keratinocytes. The overall goal of the studies is to understand the degree to which HIF-1 alpha regulates biological processes in physiological settings such as the epidermis, as well as the mechanisms by which it acts, and how this phenomenon contributes to skin growth and differentiation in both homeostasis and disease.