Dr. Ferhaan Ahmad's Cardiovascular Genetics laboratory uses a wide range of techniques in human and mouse genetics to elucidate the pathogenesis of hereditary cardiovascular diseases, including the following:
Mutations are mapped and identified in human families and individual patients with cardiovascular disorders. In addition, the laboratory uses gene targeting and transgenic technology to generate novel mouse models carrying mutations previously identified in humans with cardiovascular diseases. These models are studied to elucidate the pathways leading from genotype to phenotype.
This research is dependent on crosstalk between clinical studies, human molecular genetic studies, animal modeling, and basic cellular and molecular studies. The laboratory welcomes collaborations with patients, clinicians, and scientists, and actively seeks patients and families with inherited cardiovascular disorders who may be interested in participating in this research.
Postdoctoral fellows and medical and graduate students in the laboratory are exposed to a breadth of techniques in statistical genetics, molecular genetics, molecular and cell biology, biochemistry, and physiology. They have the opportunity to pursue projects with clinical or basic orientations, within a multidisciplinary "bedside to bench to bedside" environment.
A selection of current projects is described below. Genetic linkage analysis and positional candidate gene analysis are being performed in two human families with ARVD. In addition, we are recruiting other families with inherited cardiovascular disorders.
The phenotype and clinical outcome of patients with cardiomyopathies vary greatly, even among members of the same family with the same mutation. Therefore, in collaboration with other investigators, we are recruiting cardiomyopathy patients and studying whether polymorphisms in candidate modifier genes (genes other than those with the primary causative mutation) can alter the cardiac phenotype, response to therapy, and survival.
Different mutations in several genes, including cardiac troponin T (TNNT2), can lead to both DCM and HCM. We have generated gene targeted ("knock-in") mouse models of several TNNT2 mutations and are performing analyses to determine how mutations in the same gene lead to distinct phenotypes. Preliminary evidence suggests that DCM-and HCM-associated mutations lead to divergent early changes in cardiac contractility and calcium (Ca2+) sensitivity at the molecular and cellular level prior to evident changes at the whole organ level. Therefore, we and our collaborators Michael Mathier, MD, and Sanjeev Schroff, PhD, are performing echocardiography, in vivo hemodynamic measurements, and biomechanical studies on cardiac myocytes, isolated hearts, and/or intact mice to uncover divergent effects of these mutations on contractility. A second hypothesis is that, as a mediator of Ca2+ regulation in the sarcomere, TNNT2 mutations cause perturbations in Ca2+ levels and transients and/or action potential propagation, leading to hypertrophy, systolic or diastolic dysfunction, and/or arrhythmias. Therefore, in collaboration with Samir Saba, MD, and Guy Salama, PhD, we are performing in vivo electrophysiological studies and optical mapping using voltage-sensitive dyes.
We and others have recently identified mutations in the gene PRKAG2 as the cause for a novel cardiomyopathy characterized by glycogen storage and ventricular preexcitation. This gene encodes the regulatory γ2 subunit of AMP-activated protein kinase (AMPK), a heterotrimeric enzyme which activates several processes to conserve and to generate energy when cellular energy levels are depleted. We and our collaborators at other institutions (Drs. Arad, Roberts, and Seidman) have constructed several transgenic mouse models of human PRKAG2 mutations. We are studying the pathogenesis of PRKAG2 cardiomyopathy in these models, determining which cardiac AMPK targets are altered by the PRKAG2 mutations.
We are currently constructing other gene targeted mouse models of human cardiomyopathies, including ARVD.
200 Lothrop Street
Scaife Hall, S-558
Pittsburgh, PA 15213-2582
Phone: 412-648-9286
Fax: 412.647.4227
E-mail: ahmadf@upmc.edu