Episodic or intermittent hypoxia (IH) is associated with many pathophysiological situations, including sleep apneas and lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Experimental studies on humans, as well as animals, have documented that IH has long term effects on the cardio-respiratory systems leading to pathophysical conditions such as hypertension. Despite its clinical significance little is known about the molecular mechanisms underlying IH. The investigators have devised a technique that exposes cells to alternating cycles of low oxygen simulating IH seen in intact animals. Using this technique, they discovered two features that distinguish IH from SH. First, for a given duration and severity of hypoxia, IH is more potent in activating gene expression. Second, increases in gene expression persisted for hours after terminating IH, a phenomenon resembling long-term facilitation (LTF). The overall goal of the current proposal is to identify the mechanisms underlying activation of gene expression by IH.

The application specifically will test the hypothesis that gene activation by IH depends on the duration of oxygenation intervening the hypoxic episodes, and reactive oxygen species (ROS) play a crucial role. The investigators will use an integrated approach to test this hypothesis using both cell culture systems and in vivo experiments on wild type and mutant mice. The current proposal focuses on the regulation of c-fos and tyrosine hydrosylase (TH) genes. The Specific Aims are: 1) To assess the importance of episodic re- oxygenation on gene induction by IH and to determine whether IH-induced elevations in mRNAs are due to increased transcription, stability or both; 2) To determine the role of reactive oxygen species (ROS) and HNE signaling pathways to gene induction by IH; 3) To examine the contribution of Ca2- dependent an HNE signaling pathways to gene expression by IH; 4) To correlate cellular effects of IH on gene expression with chronic systemic responses to IH in intact animals using c-fos knockout mice.

R01HL066448

2000-09-30

2004-08-31