PRKAR1A deficiency delays postnatal heart growth

Primary author: Yuening Liu
Faculty sponsor: Zhaokang Cheng

Primary college/unit: College of Pharmacy and Pharmaceutical Sciences
Campus: Spokane

Abstract:

Aims: Protein kinase A (PKA) activity is pivotal for functioning of the human heart, and its dysregulation has been implicated in cardiac pathologies. PKA regulatory subunit 1a (R1a, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) in young adults, and may die prematurely from cardiac complications such as heart failure. However, no cardiac defect has been reported in adult animal models of PRKAR1A deficiency.
Methods and Results: To investigate the impact of PRKAR1A deficiency, we generated cardiac-specific PRKAR1A heterozygous knockout mice by breeding the floxed PRKAR1A mice with the Mlc2v-Cre mice. We also studied a cohort of young CNC patients with PRKAR1A mutations or deletions. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight and cardiomyocyte size without altering contractile function at 3 months of age. Importantly, left ventricular mass was reduced in young patients diagnosed with CNC. Cardiomyocyte hypertrophy in response to activation of the a1-adrenergic receptor, which is necessary for heart growth after birth, was completely abolished by silencing of PRKAR1A, or stimulation with the PKA activator forskolin. Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, leading to suppression of mitochondrial fission and inhibition of cardiomyocyte hypertrophy.

Conclusions: PRKAR1A deficiency impedes postnatal myocardial development and physiological hypertrophy through modulation of mitochondrial dynamics. These findings provide a potential novel mechanism for the cardiac manifestations associated with CNC.

Evaluating the impact of pharmacist-led HIV and HCV screening and education on adults experiencing homelessness in Spokane, Washington

Primary author: Sorosh Kherghehpoush
Co-author(s): Kimberly McKeirnan

Primary college/unit: College of Pharmacy and Pharmaceutical Sciences
Campus: Spokane

Abstract:

Over half a million people experience homelessness on a given night in the United States. As a result of increased exposure to disease, violence, unsanitary conditions, stress, malnutrition and substance abuse, homeless persons experience medical problems and treatment complications at higher rates than the general population.

Chronic disease states that require uninterrupted treatment and high rates of adherence, such as Hepatitis C and HIV/AIDS, are more difficult to control in those with unstable housing. Individuals living with HIV/HCV who are unaware of their infection are more likely to transmit these diseases than persons who are aware of their HIV/HCV diagnosis. Gay and bisexual men account for the majority of new HIV diagnoses followed by injection drug users who account for the majority of Hepatitis C infection, two sub-populations that are also disproportionately affected by homelessness.

Given the barriers to clinical engagement and the persistent stigma, HIV and HepC provide an important opportunity for pharmacist involvement.

In this research study, participants will undergo an HIV and HCV point-of-care screening test complimented with comprehensive HIV and HCV education and personalized risk mitigation strategies. Study participants who have a reactive screening are referred to a partnering HIV/HCV specialist to establish care and the local health district for anonymous partner notification.

There are wide-ranging implications associated with this study. Early recognition and treatment to reduce transmission. Increased access to care even for the uninsured. Lower healthcare costs associated with emergency room visits. improved health literacy of a vulnerable population.

De-escalation of antibiotic therapy in acute exacerbation of COPD (AECOPD)

Primary author: Anne Keef
Faculty sponsor: Dr. Megan Undeberg

Primary college/unit: College of Pharmacy and Pharmaceutical Sciences
Campus: Spokane

Abstract:

COPD patients are at increased risk of pulmonary infections secondary to their underlying pathology of the disease: compromised lung function coupled with increased inflammation and mucus production within the lungs provides for a breeding ground for infection. COPD patients are at increased risk of infection by M. catarrhalis, H. influenzae, and S. pneumoniae. Typically, these pathogens induce upper respiratory tract infections. In the COPD patient, however, the compromised lung function and decline in innate respiratory elevator clearing functions results in an increased risk for bacteria to invade the lower respiratory tract and induce inflammation and infection. Additionally, infection with Pseudomonas is not uncommon in COPD patients with more severe symptoms at baseline and especially those with recurrent infections. Regardless of the pathogenic cause, the resultant increase in inflammation in the lungs places the COPD patient at increased risk for further decompensation and increased morbidity. As a result, when a patient presents with cardinal symptoms of an infection inducing an acute exacerbation of COPD (AECOPD), it is not uncommon for a patient to be started on empiric, broad spectrum antibiotic therapy with Pseudomonas coverage, pending sputum culture results. However, once sputum cultures have resulted, antimicrobial therapy is not always refined to correlate with the pathogen present. Our project proposes looking at AECOPD admissions for the first quarter of 2019, initial antibiotic choice, sputum culture results, and subsequent change or no change to antibiotic therapy. Results from this information will guide antimicrobial stewardship and provider education.