Dr. Glenn Radice, PhD
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The Radice Laboratory is interested in understanding molecular mechanisms of cardiovascular development and physiology and their implications for human disease. Cadherins form intercellular junctions, which serve both as mechanical linkages between cells and as signaling hubs that modulate intracellular signal transduction. Transgenic and knockout mouse models are used to investigate the function of the N-cadherin/catenin cell adhesion complex in embryonic, fetal and adult heart. We have shown that the N-cadherin/catenin complex is critical for maintaining normal heart rhythms and that loss of the adhesion complex leads to sudden arrhythmic death. Sudden death in this model is attributed to gap junction remodeling that leads to decreased ventricular conduction velocity and re-entrant arrhythmias. The role of gamma-catenin or plakoglobin in the etiology of arrhythmogenic cardiomyopathy is currently under investigation.
More recent work focuses on the role of the cytoskeletal linker proteins, alpha-catenins, in cardiac development and regeneration. We discovered that ablating alpha-catenins stimulates cardiomyocyte proliferation by allowing Yap, a transcriptional co-activator, to accumulate in the nucleus where it binds to Tead transcriptional factors to induce expression of cell cycle regulators and other target genes. In preclinical studies, alpha-catenin mutant mice exhibit enhanced cardiomyocyte proliferation and improved contractility following myocardial infarction. We are currently investigating whether cytoskeletal remodeling regulates Yap cellular distribution in alpha-catenin-deficient cardiomyocytes.
Changes in cell-cell and cell-matrix adhesion accompany the transition from benign tumors to invasive, malignant cancer and the subsequent metastatic dissemination of tumor cells. Cadherin switching (E- to N-cadherin) is a hallmark of tumor progression, yet it is poorly understood how N-cadherin affects tumor cell behavior in vivo. We have shown that interfering with N-cadherin is sufficient to prolong survival of mice suffering from highly metastatic pancreatic cancer.
Opportunities are available to analyze transgenic and knockout mice that serve as models of human disease. Specific projects involve investigating alpha-catenins in cardiac regeneration, plakoglobin in arrhythmogenic cardiomyopathy, and N-cadherin in pancreatic cancer metastasis. Projects are tailored to students’ experience and interest.