Hassan Ashraf

 Hassan Ashraf
Mentor: Dr. Hideko Kasahara
College of Medicine
 
"Learning biological science through text books is useful for knowledge but doing so doesn't provide a meaningful experience. I was interested in seeing what it took to get the information into the text books. Genetics is the future of medicine and I've always had an interest in cardiac physiology. Those two combined is exactly what I get to work with on a daily basis and for that I am very lucky. It is a wonderful experience."

Major

Biology

Minor

History

Research Interests

  • Human Physiology
  • Genetics
  • Clinical

Academic Awards

  • UF University Scholars Program

Organizations

  • Islam on Campus
  • Pakistani Students Association
  • Heal the World

Volunteer

  • Project Downtown
  • Rahma Mercy Clinic
  • Peru Medical Mission Trip

Hobbies and Interests

  • Research
  • Volunteer
  • Motorcycles

Research Description

Mouse Model of Human Congenital Heart Disease: Heterozygous Nkx2-5 Missense Mutation
A growing number of autosomal dominant mutations in the transcription factor NKX2-5 are linked to congenital heart disease. Genetically engineered mouse models are extremely useful for modeling human disease; however multiple heterozygous Nkx2-5 knockout mouse lines show lower penetrance and severity than in humans with Nkx2-5 mutations. Thus, we hypothesized that disease-causing mutations are not simple loss-of-function mutation. To test this hypothesis, our lab generated a novel heterozygous knock-in mouse model by introducing in mice the same point mutation found in humans: 52ArgGly point mutation in the homeodomain. Expression of subsets of known Nkx2-5 targets is markedly downregulated in Nkx2-5R52G/+ hearts (knock-in), notably, among them, atrial natriuretic factor. We will focus on three disease phenotypes that are most prevalent and critical for survival observed in human patients with NKX2-5 mutations. Incidence of cardiac anomalies including atrial and ventricular septal defects will be examined in Aim 1. Ventricular dysfunction with hyper-trabeculation that can be secondary to volume-overload from left-right shunt, or primary disease resulting from Nkx2-5 mutations is also examined in Aim 1. In Aim 2, we will ask whether Nkx2-5R52G/+ mice demonstrate progressive atrio-ventricular block that advances to III° block. Currently I am working on Aim 1 to examine whether Nkx2-5R52G/+ hearts demonstrate cardiac anomalies. The mice hearts are taken at two time points: shortly after birth and postnatal day 10. These two time points are chosen because some newborn mice are found dead or cyanotic with profound cardiac anomalies. Postnatal day 10 was selected to examine inter-atrial communication that is normally observed until postnatal day 7 according to our previous study. After taking pictures of the whole hearts, they are examined in serial tissue sectioning to find atrial and ventricular septal defects. In addition, the hearts are measured for their length, width, area, septum size, compact layer and trabecular layer area size. Aim 1 has been underway since Fall 2012 and is expected to finish by the end of Summer 2013. Aim 2 is designed to examine whether Nkx2-5R52G/+ mice demonstrate progressive atrioventricular (AV) block that advances to III°. We will perform serial surface ECG and telemetric ECG recording of heterozygous Nkx2-5R52G/+ and wild-type mice in summer to fall 2013. Importantly, we will record ECGs at several time points (i.e., 3, 6, 12 months of age) and examine whether atrio-ventricular conduction block is progressive. Our previous studies have shown that only homozygous but not heterozygous tamoxifen-inducible Nkx2-5 knockout mice result in AV block. Of note, germline Nkx2-5-/- mice are embryonic lethal (die around embryonic day 10.5), thus these mice cannot be utilized for the studies described above.Upon successful completion of our aims, we will have established a mouse model of human disease in which disease progression and underlying pathogenesis can be examined, which cannot be done in humans.