Kathryn Schunke

The Schunke Laboratory focuses on molecular, transcriptional, and epigenetic targets of myocardial and cerebrovascular disease to expand understanding of the mechanisms of ischemic, hypoxic, cardiometabolic and autonomic dysfunction.  We use mouse and rat models of disease, as well as immortalized cell lines, primary tissue culture, and human inducible pluripotent stem cells (iPSCs) to characterize temporal pathology states, discover disease mechanisms, and determine therapeutic targets to prevent and treat disease progression.  Our laboratory utilizes a variety of techniques such as In vivo echocardiography, implantable telemetry for ECG and blood pressure measurement, Ex-vivo and In-vitro functional and molecular assays, as well as next-generation sequencing technology for gene expression and chromatin biology analysis.

We currently have 3 main research areas:

(1) Regulation of the HIF-1 response by chromatin reader, PRKCBP1 (Zmynd8)

(2) Autonomic dysfunction in:

(a) Type 2 diabetes mellitus, and (b) Sleep apnea

(3) Perinatal Sleep Apnea: Epigenetics in the Basis for Adult Disease Susceptibility

It has recently been discovered that some of the chromatin modulatory machinery essential for proper development, maintenance and repair of the genome plays a previously unappreciated role in the pathogenesis of ischemic heart disease. Our current research focuses on understanding the epigenetic regulation of HIF in response to myocardial infarct. Using a combination of animal, molecular and next-generation sequencing techniques, we aim to identify targets for new therapeutic approaches to ischemic heart disease.

(2) Autonomic dysfunction:
The autonomic nervous system regulates all aspects of normal cardiac function and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases including heart failure, myocardial infarct, diabetes, atherosclerosis, and sleep apnea.  As such, the value of neuroscience-based cardiovascular therapeutics is increasingly evident.

(a) Type 2 diabetes mellitus

Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk-reduction strategies beyond glycemic control. The prevalence of diabetes continues to rise – It is estimated that as many as one in three US adults will have diabetes by 2050 if the current trend continues. The majority (90%) of diabetes is type 2 diabetes mellitus (T2DM) and is one of the leading epidemics in human history closely associated with obesity.

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy (CAN), defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The sympathetic overactivity and reduced parasympathetic cardiac vagal activity is correlated with life-threatening complications (arrhythmias, silent myocardial ischemia, and sudden death) and other microangiopathic comorbidities. In recent years, much attention has been directed to early warning signs of CAN, detectable in the first years after diabetes onset by means of validated cardiovascular reflex tests. Such warning signs include reduced heart rate variability (HRV) during deep breath, prolongation of QT interval, temporally followed by resting tachycardia, impaired exercise tolerance, and decreased baroreflex sensitivity with consequent abnormal blood pressure regulation, and orthostatic hypotension.

The mechanisms responsible for the decrease in parasympathetic activity to the heart in diabetes are unknown, and this lack of understanding is a roadblock to this potential novel therapeutic avenue. In this project, we aim to identify functional and transcriptional changes of neurons in the paraventricular nucleus of the hypothalamus and characterize how downstream networks in the brainstem are affected by T2DM. This central drive network ultimately determines post-ganglionic signals the cardiac vagal neurons receive and thus how heart conductivity and function are altered.

(b) Sleep apnea

Patients suffering from obstructive sleep apnea (OSA) have a 3-fold increase in cardiovascular mortality, yet very little is known regarding how OSA directly increases the risk for myocardial injury and disease. A goal of this project is to identify the specific impact of OSA on the cardiac function of rats exposed to chronic intermittent hypoxia (CIH), a model of OSA. Our studies will also test the innovative hypothesis that appropriately timed activation of a small population of hypothalamic paraventricular neurons will slow the development of, or reverse, the deleterious autonomic and cardiac function alterations that occur during OSA.

(3) Perinatal Sleep Apnea: Epigenetics in the Basis for Adult Disease Susceptibility
Obstructive sleep apnea (OSA) is recognized as an independent and important risk factor for neurocognitive, behavioral, and cardiovascular diseases such as sudden death, hypertension, arrhythmias, myocardial ischemia, and heart failure. Pediatric OSA is a frequent condition affecting 2–4% of children and is associated with an increased risk for both immediate and adult-onset end-organ dysfunction such as accelerated atherosclerosis, endothelial dysfunction, diabetes and obesity. Adult-onset chronic non-communicable diseases can originate from early life through the “developmental origins of health and disease” whereby an insult applied at a developmental window causes long-term effects on the structure or function of an organism.

Clinical data and animal models show that chronic intermittent hypoxia (CIH) is a major contributor to the deleterious consequences of OSA. The repetitive occurrence of hypoxia-reoxygenation sequences reduces oxygen tension in the blood, generates reactive oxygen species (ROS), and thus stabilizes hypoxia-inducible factor (HIF-1) which is the master transcription factor involved in oxygen homeostasis, regulating a variety of adaptive responses to hypoxia, including metabolic reprogramming and cell survival. The exact mechanisms of early-life origin of adult disease are unclear, but a likely mediator at the molecular level is epigenetic dysregulation of gene expression as a driver of early-life programming of adult-onset diseases. For example, a recent study demonstrated that adult rats that were exposed to CIH as neonates exhibited exaggerated responses to hypoxia resulting in irregular breathing, apnea, and hypertension. The enhanced hypoxic sensitivity was associated with elevated ROS, and decreased expression of the antioxidant enzyme SOD2 which was hypermethylated at the DNA transcription start site. Treatment with a DNA methylation inhibitor reversed these effects. These findings implicate a role for epigenetic regulation of the genome in mediating neonatal programming of hypoxic sensitivity and present evidence for targeted therapy of epigenetic marks for re-programming. Moreover, the role and consequences of HIF-1 stabilization and ROS production in neonates exposed to CIH, a significant and clinically relevant question for the epigenetic perinatal field, remains unknown.

Our goals are to identify the plasticity of cardiac alterations resulting from neonatal exposure to CIH, a well characterized model to phenocopy OSA. Our hypothesis is that CIH modifies the epigenome during critical developmental windows, resulting in maladaptive regulation of genes with consequences that persist for much longer periods than the duration of the hypoxic stimulus. These epigenomic changes ultimately reprogram the ‘histone code’, negatively influencing metabolic and cardiovascular status into adulthood, and predispose children to late adverse health events. We aim to identify changes in epigenetic regulation of gene expression and determine if those changes are maintained and contribute to poor cardiovascular health in adulthood. These data will identify druggable epigenetic targets for therapeutic intervention before the onset of adult disease

Select Publications

Dyavanapalli J, Rodriguez J, Rocha dos Santos C, Escobar JB, Dwyer MK, Schloen J, Lee K, Wolaver W, Wang X, Dergacheva O, Michelini LC, Schunke KJ, Spurney CF, Kay MW, Mendelowitz D. Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure. JACC Basic Transl Sci. 2020 May 25

Schunke KJ, Walton CB, Veal DR, Mafnas CT, Anderson CD, Williams AL, Shohet RV. Protein Kinase C Binding Protein 1(PRKCBP1) Inhibits Hypoxia Inducible Factor 1 (HIF-1) in the Heart.Cardiovasc Res. 2018 Nov 5

Williams AL, Khadka V, Tang M, Avelar A,Schunke KJ, Menor M, Shohet RV. HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction. Physiol Genomics. 2018 Apr 13

Chen L, Xu X, Zeng H, Kannie W, Chan Y, Yadav N,Schunke KJ, Faraday NF, Van Zijl P, Xu J. Separating out fast and slow chemical exchange using off-resonance variable delay multiple pulse (VDMP) MRI. Magn Reson Med. 2018 Feb 5

Schunke, K.J., Rosati L.M., Herman, J.M., Zahurak, M.L., Usach, I., Klein, A., Rosati, L.M., Yeo, C.J., Korman, L.T., Laheru, D.A., Abrams, R.A. Long-term analysis of Two Prospective Studies that Incorporate Mitomycin C into an Adjuvant Chemoradiation Regimen for Pancreatic and Periampullary Cancers. Adv in Radiat Oncol. 2017 Aug 3

Schunke KJ, Toung TK, Zhang J, Pathak A, Zhang J, Koehler R, Faraday N. A Novel Atherothrombotic Model of Ischemic Stroke Induced by Injection of Collagen into the Cerebral Vasculature. J Neurosci Methods. 2014 Oct 11

Faraday N,Schunke KJ, Saleem S, Fu J, Wang B, Zhang J, Morrell C, Dore S. Cathepsin Gdependent modulation of platelet thrombus formation in vivo by blood neutrophils PlosOne. 2013 Aug 5

Schunke KJ, Coyle L, Merrill GF, Denhardt DT. Acetaminophen attenuates doxorubicin- induced cardiac fibrosis via osteopontin and GATA4 regulation: Reduction of oxidant levels. J Cell Physiol. 2013 Oct

Baliga SS, Jaques-Robinson KM, Hadzimichalis NM, Golfetti R, Merrill GF.  Acetaminophen reduces mitochondrial dysfunction during early cerebral postischemic reperfusion in rats. Brain Res. 2010 Jan 14

Chakir K, Daya SK, Aiba T, Tunin RS, Dimaano VL, Abraham TP, Jaques-Robinson KM, Lai EW, Pacak K, Zhu W, Xiao R, Tomaselli GF, Kass DA. Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy. Circulation. 2009 Mar 10

Jaques-Robinson KM, Golfetti R, Baliga S, Hadzimichalis NM, Merrill GF. Acetaminophen is cardioprotective against H2O2- induced injury in vivo. Exp Biol Med (Maywood). 2008 Oct

Hadzimichalis NM, Baliga SS, Golfetti R, Jaques KM, Firestein, BL, Merrill GF. Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore induced apoptotic pathway. Am J Physiol Heart Circ Physiol. 2007 Dec