Post-Doctoral Fellow (Transfer) for Kimberly Smith in support of: Molecular Mechanisms of Notch Signaling-Enhanced Store-Operated Calcium Entry

Project: Research project

Project Details


Chronic exposure to hypoxic conditions is a major cause for elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with hypoxia-induced pulmonary hypertension (HPH). Elevated PVR increases right heart afterload and over time results in right ventricular hypertrophy and eventually right heart failure and death. Increased PVR is due to sustained vasoconstriction and excessive vascular remodeling. The disruption of the balance between proliferation and apoptosis in pulmonary arterial smooth muscle cells (PASMC) is central to the pathogenesis of vascular remodeling in HPH. Increased cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC is a major trigger for vasoconstriction and a key stimulus for cell proliferation and migration, which contribute to vascular remodeling. Store-operated Ca2+ entry (SOCE), an important mechanism for controlling [Ca2+]cyt, is enhanced in PASMC from patients with pulmonary hypertension (PH). Additionally, PH-PASMC have increased expression of the canonical transient receptor 6 (TRPC6) channel, which may to contribute to SOCE. Notch signaling is important for controlling cell proliferation and we have previously shown that Notch3 is upregulated in patients with PH and in mice with HPH. Our preliminary data indicate that hypoxia-induced enhancement of SOCE and expression of TRPC6 is dependent on Notch signaling and that hypoxia-induces a direct interaction between NICD and TRPC6 in PASMC. Therefore, we hypothesize that hypoxia activates Notch signaling by upregulation of Notch receptors and ligands which enhances SOCE by both direct functional interaction with TRPC6 and by transcriptional upregulation of TRPC6. The resulting increase in [Ca2+]cyt contributes to the development of HPH. Understanding the molecular mechanisms by which hypoxia-induced Notch signaling activation leads to increased [Ca2+]cyt and cell proliferation is critical to our elucidation of the pathogenesis of HPH. Specific Aim 1: To determine whether hypoxia activates Notch signaling by upregulation of Notch receptors, ligands, and/or γ-secretase, and to whether activation of Notch signaling by hypoxia is mediated by HIF1α. Specific Aim 2: To investigate which domains are required for the interaction of NICD and TRPC6, and determine whether this interaction is functionally required for hypoxia-enhanced SOCE. Additionally, we will determine how Notch signaling regulates transcription of TRPC6.
Effective start/end date9/1/1412/31/14


  • American Heart Association Midwest Affiliate (13POST14700013)


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