Mentor: Dr. Hideko Kasahara
College of Medicine
"Being able to apply knowledge from my courses and enhance my understanding of these concepts through research is a valuable experience. I wanted to be able to perform hands-on experiments and examine samples in the lab and critically think of explanations, reasons, or alternative solutions to our findings. This mindset of thinking is more involved than the traditional classroom and has allowed me to further develop as a student. It is extremely rewarding and an opportunity to contribute new knowledge to our existing literature."
- Human Physiology
- Cardiovascular diseases
- Florida Bright Futures Scholarship
- President's Honor Roll
- UF Presidential Service Award
- University Scholars Program
- Mobile Outreach Clinic
- Habitat for Humanity
Hobbies and Interests
- Jet Skiing
Role of phosphorylation of Z-disc Protein Xin Actin-Binding Repeat-containing Protein 1 (XIRP1) in sarcomere organization
In 2010, the overall death rate from cardiovascular disease was 235.5 per 100,000. 1 in 9 of these deaths were due to heart failure, an inability of the heart to sufficiently pump blood to meet the body’s circulatory demand. The dynamics of cardiac contraction and relaxation are fundamentally related to actin-myosin interactions, which are regulated by a multitude of factors. Our previous studies demonstrated that cardiac myosin light chain kinase (cMLCK) that phosphorylates myosin light chain2 (MLC2) is involved in enhancement of sarcomere organization. Pressure overload reduces cardiac myosin light chain kinase (cMLCK) by ~80% within 1 week and persists. To mimic acute cMLCK reduction, the Mylk3 gene that encodes cMLCK was inducibly ablated in adult mice. Within 1 week, these mice exhibited heart failure with myocyte atrophy and were unable to adapt to pressure overload. To capture whole heart phosphorylation status in failing hearts, we screened for additional phosphopeptides in cMLCK-ablated hearts using phosphopeptide-enrichment followed by mass spectrometry (MS) analysis. We found an increase in phosphorylation of Xin Actin-Binding Repeat-containing protein (XIRP1) at serine 295. Western blotting confirmed an increased phosphorylation of S295 and level of protein expression of XIRP1 in cMLCK-ablated hearts 1 week after tamoxifen-injection (Figure 1). XIRP1 is localized in cardiac z-discs, an area recognized as a nodal point in cardiomyocyte signal transduction, and binds to and stabilizes the actin-based cytoskeleton. Xin repeats has been shown to bind F-actin. Its expression has been shown to increase in compensatory hypertrophy, but is decreased in decompensated heart failure. Little is known about the post-translation mechanism, including phosphorylation that regulates XIRP1 function. We hypothesize that phosphorylation of XIRP1 with increased level of protein expression is activated in cMLCK-ablated hearts to compensate and protect the heart by enhancing sarcomere organization. In Aim 1, we will examine sarcomere organization and cardiac function in cultured cardiomyocytes and in vivo mouse by overexpressing wild-type, non-phosphorylatable (295Ser→Ala) and phospho-mimetic mutant (295Ser→Glu) XIPR1 using adenovirus and AAV respectively. To accomplish Aim 1, we have already generated adenoviruses encoding these three XIRP1 constructs. In Aim 2, we examine the expression and level of S295 phosphorylation in normal and ischemic failing hearts from transplant patients. We will keep in mind of the potential opposite effects of XIRP1 phosphorylation in sarcomere disorganization. Upon successful completion of our aims, we will be able to determine if XIRP1 phosphorylation is playing a role in sarcomere organization in mice and determine a correlation in human heart failure.