N. Muge Kuyumcu-Martinez, Ph.D., Assistant Professor
Our laboratory’s main focus is to understand the regulation of alternative splicing (AS) networks in the heart and how dysregulation of AS impacts heart function and development. Specifically, we are interested in identifying signaling pathways that control differential expression of alternatively spliced variants in the heart.
We are currently pursuing two different aspects of AS regulation.
1. Regulation of AS networks by PKC in developing heart
Our data indicate that the protein kinase C (PKC) signaling is critical for AS transitions during rat and mouse heart development. We are systematically investigating a cause and effect relationship between PKC and synchronized AS networks during murine heart development. We are also testing RNA binding protein substrates of PKC in developing heart. Our aim is to identify a regulatory circuitry that controls gene expression via AS during heart development and cardiac differentiation.
AS can alter expression of genes drastically by removing or including alternative exons that correspond to the sequences responsible for mRNA stability and translatability. It can also modify the function of proteins by eliminating exons that code for essential domains. Even though AS is critical for gene regulation, the mechanisms that coordinate AS events in the heart is not well understood. Identifying AS events with direct impact on gene function may provide ways to treat congenital and adult heart diseases, which can be caused by mutations that affect proper splicing.
2. Dysregulation of AS in diabetes
Since chronic activation of PKC is a major contributor to cardiovascular complications of diabetes, we are testing whether PKC causes misregulation of AS in diabetic hearts. Our data show that aberrantly spliced isoforms of genes are expressed in diabetic heart tissues. We are further pursuing the consequences of AS defects in diabetes and analyzing the RNA binding proteins involved in this process.
Diabetes is a costly health care problem affecting 8.3% of the US population. The majority of the diabetes patients die from cardiovascular complications. Defining AS events that promote abnormal gene expression in diabetic hearts may reveal novel ways such as oligo-based therapy to correct splicing defects and ultimately prevent/treat cardiovascular complications of diabetes.
In the laboratory, we use several different model systems including cultured cells, transgenic and knockout mouse models, and rat models to understand the fundamental questions about AS regulation in the heart.
Current Lab Members
Sunil Verma, PhD