Proliferation and Differentiation of Human Stem Cells by Agonism of AT1 and AT2

Grant Winners

  • James R. Munoz, Ph.D. – Farquhar College of Arts and Sciences
  • Robert C. Speth, Ph.D. – College of Pharmacy
  • Zara Khan – Farquhar College of Arts and Sciences
  • Andrea Linares – Farquhar College of Arts and Sciences

Deans

  • Don Rosenblum, Ph.D. – Farquhar College of Arts and Sciences
  • Lisa Deziel, Ph.D., Pharm. D. – College of Pharmacy

Abstract

Award Winners

Angiotensin II is a well described potent vasoactive hormone in the renin-angiotensin system that regulates blood pressure. Altered levels of angiotensin expression have been directly linked to peripheral diseases such as coronary artery disease, kidney disease, diabetes, and central diseases such as stroke, dementia, and neurodegenerative diseases. As neural stem cells reside in highly vascularized niches, it follows that changes in blood pressure may alter their function. Alterations in neural stem cell niches have been associated with spatial learning and memory and cognition. Recently, the angiotensin II receptors AT1 and AT2 were found to be expressed on rat neuronal stem cells. We propose to examine how selective activation of the angiotensin system through either the AT1 or AT2 receptor affects human neural stem cell proliferation, differentiation, and survival. Based on known signaling pathways in neural stem cells that promote either proliferation or differentiation and similarities with signaling pathways for each receptor, we hypothesize that agonism of the AT1 receptor will promote proliferation and decrease cell death, while agonism of the AT2 receptor will promote differentiation of neural stem cells. As differentiation is often associated with increased cell death, we also expect to observe increased cell death following agonism of the AT2 receptor. Assays will include thymidine analog incorporation assays, immunofluorescence, and cell death assays to examine changes in proliferation, differentiation, and cell death on human neural stem cells following selective agonism of either the AT1 or AT2 receptor in both proliferating and differentiating conditions. These findings may demonstrate a role for theangiotensin system as a novel target to regulate neural stem cell function with implications for enhancing age-related detriments in learning and memory, regeneration following injury, and therapeutic intervention across a broad spectrum of neurodegenerative diseases.