Discoveries at the Davis Heart and Lung Research Institute

Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose 

Kristy Townsend, PhD

"Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small-fiber innervation and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new therapies are needed for treatment of this condition affecting 20-30 million Americans. Here, we validated a gene therapy approach using an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) directly to scWAT to improve tissue-specific PN as a proof-of-concept approach."

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The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity

George Kyriazis, PhD

"The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception."

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Endocardial HDAC3 is required for myocardial trabeculation 

Deqiang Li, PhD & Vidu Garg, MD

"Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells… Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.”

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Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults 

Przemyslaw Radwanski, PharmD, PhD, Rengasayee Veeraraghavan, PhD, Thomas Hund, PhD, Seth Weinberg, PhD & Drew Nassal, PhD

"In this study, the authors sought to provide evidence implicating remodeling of Na+ - and Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias."

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Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune 

Rama Mallampalli, MD, James Londino, PhD, Joseph Bednash, MD, Laszlo Farkas, MD & Mauricio Rojas, MD

“The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties… Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.”

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Immune evasion, infectivity, and fusogenicity of SARS-CoV-2 BA.2.86 and FLip variants

Richard Gumina, MD, PhD, Rama Mallampalli, MD, Jeffrey Horowitz, MD, & Joseph Bednash, MD

“Overall, our study underscores the importance of SARS-CoV-2 variant surveillance and the need for updated COVID-19 vaccines.”

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The deubiquitinase USP40 preserves endothelial integrity by targeting the heat shock protein HSP90β

Jing Zhao, MD, PhD, Yutong Zhao, MD, PhD, & Rama Mallampalli, MD

“…these data reveal a critical protective role of USP40 in vascular injury, identifying a unique mechanistic pathway that profoundly impacts endothelial function via DUBs.”

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Evidence for the Association Between Adverse Childhood Family Environment, Child Abuse, and Caregiver Warmth and Cardiovascular Health Across the Lifespan: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 

Joshua Joseph, MD

“Although risky family environmental factors in childhood increase the odds of poor longitudinal adult CVH, caregiver warmth may increase the odds of CVH, and socioeconomic attainment in adulthood may contextualize the level of risk.”

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Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor

Kristin Stanford, PhD, Dmitry Terentyev, PhD, Loren Wold, PhD, Thomas Hund, PhD, Mark Ziolo, PhD, & Drew Nassal, PhD

“These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations.”

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Abnormal Progenitor Cell Differentiation and Cardiomyocyte Proliferation in Hypoplastic Right Heart Syndrome

Mingtao Zhao, DVM, PhD, Vidu Garg, MD, & Samir Ghadiali, PhD

“These results indicate that PA-IVS iPSC-CMs are less proliferative and metabolically more advanced in mitochondrial respiration, which may lead to reduced cardiomyocyte proliferation and enhanced maturation.”

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Troponin I Tyrosine Phosphorylation Beneficially Accelerates Diastolic Function

Brandon Biesiadecki, PhD & Jill Rafael-Fortney, PhD

“We have demonstrated that tyrosine kinase phosphorylation of TnI is a novel mechanism to directly and beneficially accelerate myocardial relaxation in vivo.”

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RAB7 Deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension

Laszlo Farkas, MD, Rama Mallampalli, MD, Ana Mora, MD, Mauricio Rojas, MD, Jeffrey Horowitz, MD & Nuo Sun, PhD

“Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level…”

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MicroRNA-1 Deficiency is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostatis

Jidong Fu, MD, Loren Wold, PhD, Peter Mohler, PhD, Tom Hund, PhD, & Isabelle Deschenes, PhD

“miR1 deficiency acts as a primary etiological factor in inducing cardiac remodeling via disrupting heart regulatory homeostasis. Achieving stable and appropriate microRNA expression levels in the heart is critical for effective microRNA-based therapy in cardiovascular diseases.”

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iCEPT Calculator: A Web-Based Application to Standardize the Calculation of Alpha Distensibility in Patients With Pulmonary Arterial Hypertension

Rebecca Vanderpool, PhD

"The interactive user interface in the iCPET calculator allows exploration of alpha distensibility using standardized methods. No significant change in alpha distensibility at follow-up suggests that alpha may be less modifiable in patients with long-standing pulmonary arterial hypertension.”

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Screening for dilated cardiomyopathy in at-risk first-degree relatives

Ray Hershberger, MD

"A multi-site study led by researchers at The Ohio State University Wexner Medical Center and College of Medicine shows the importance of clinical screening for dilated cardiomyopathy (DCM) in family members of patients diagnosed with the heart muscle disease."

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Engineered extracellular vesicles derived from dermal fibroblasts attenuate inflammation in a murine model of acute lung injury

Higuita-Castro, Gallego-Perez, Englert, Ghadiali, and Wold

"Therapeutic nanocarriers engineered from adult skin cells can curb inflammation and tissue injury in damaged mouse lungs, new research shows, hinting at the promise of a treatment for lungs severely injured by infection or trauma."

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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Willa Hsueh, MD

"We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits."

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Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators

Rama Mallampalli, MD

"Given the role of 15-lipoxygenase (15LOX) association with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) in initiating ferroptosis-specific peroxidation of polyunsaturated PE, we propose a strategy of discovering antiferroptotic agents as inhibitors of the 15LOX/PEBP1 catalytic complex rather than 15LOX alone."

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An integrated cell atlas of the lung in health and disease

Mauricio Rojas, MD

"The largest and most comprehensive cell map of the human lung was announced recently in a manuscript published in Nature Medicine. Revealing the great diversity of cell types in the lung and key differences between health and disease, the Human Lung Cell Atlas will be a valuable resource for lung researchers."

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Structural insights into actin isoforms

Sarah Heissler, PhD and Krishna Chinthalapudi, PhD

"These results are an important foundation for further work on actin and how it interacts with other proteins. The structures could help researchers design new tools that can be used to target specific isoforms of actin in different types of laboratory experiments."

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CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

Ana Mora, MD and Mauricio Rojas, MD

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NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling

Przemyslaw Radwanski, PharmD, PhD, Rengasayee Veeraraghavan, PhD, Sandor Gyorke, PhD, Dmitry, Terentyev, PhD, and Jonathan Davis, PhD

A study by researchers at The Ohio State University reveals new insights into the cause of certain cardiac arrhythmia disorders. The findings may lead to new treatments.

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Age-related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment

Kristy Townsend, PhD

"We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis."

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E-cigarette vapor exposure in utero causes long-term pulmonary effects in offspring

Matthew Gorr, PhD

"Our work shows that in utero exposure to e-cigarette vapor, regardless of nicotine presence, causes lung dysfunction and structural impairments that persist in the offspring to adulthood."

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Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants

Richard Gumina, MD, PhD

"Mounting concern about the long-term efficacy of messenger RNA (mRNA) booster vaccines against coronavirus disease 2019 (Covid-19)1 has been exacerbated by the recent emergence of the B.1.1.529 (omicron) subvariants BA.2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have high degrees of immune escape..."

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Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity

Willa Hsueh, PhD

"Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans....In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance."

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BEX1 is a critical determinant of viral myocarditis

Federica Accornero, PhD

"Our laboratory has discovered Brain Expressed X-linked protein 1 (BEX1) as a novel stress-regulated pro-inflammatory factor in the heart. Here we report that BEX1 plays a cardioprotective role in the heart during viral infection."

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Estrogen Receptor-β Agonists Modulate T-Lymphocyte Activation and Ameliorate Left Ventricular Remodeling During Chronic Heart Failure

Shyam Bansal, PhD

"Researchers at The Ohio State University Wexner Medical Center and College of Medicine have developed a novel drug molecule that targets T-cells causing inflammation in heart failure patients, stopping further progression of the disease."

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Prevalence and cumulative risk of Familial idiopathic dilated cardiomyopathy

Ray Hershberger, MD

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MicroID2: A novel biotin ligase enables rapid proximity-dependent proteomics. Mol Cell Proteomics

James Londino, PhD

"Recent advancements in proximity dependent biotinylation tools have improved efficiency and timing of labeling, allowing for measurement of interactions on a cellular timescale. However, issues of size, stability, and background labeling of these constructs persist. Here we modified the structure of BioID2, derived from A. aeolicus BirA, to create a smaller, highly active, biotin ligase that we named MicroID2."

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Exerkines in health, resilience and disease

Kristin Stanford, PhD

"This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions."

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Outcomes of Cooking Matters for diabetes: A 6-week randomized, controlled cooking and diabetes self-management education

Joshua Joseph, MD

"Researchers at The Ohio State University Wexner Medical Center and College of Medicine partnered with Local Matters on a study that tested whether a cooking intervention that provided food – along with diabetes self-management education to encourage healthy eating and physical activity – would improve A1C hemoglobin levels and diabetes management."

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Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy

Jill Rafael-Fortney, PhD

"Anti-inflammatory properties of MRAs and different limb and respiratory muscle responses to glucocorticoids should be considered when optimizing treatments for DMD patients."

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Exosome Delivery to the Heart: What Can Brown Fat Do for You? 

Kristin Stanford, PhD

"Featured editorial by Kristin Stanford, PhD and collaborator Michael Tranter, PhD discussing how brown adipose tissue, or “good” fat, communicates to other tissues throughout the body." 

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A data-assimilation approach to predict population dynamics during epithelial-mesenchymal transition

Seth Weinberg, PhD

"The Weinberg lab applies an advanced mathematical approach analogous to forecasting the weather to predict how epithelial cells transition to a mesenchymal state."

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