The NJ Alliance for Clinical and Translational Science (NJ ACTS) experience: Responding at "warp speed" to COVID-19.

Introduction: The COVID-19 pandemic's need for life-saving treatments and a "warp speed" vaccine challenged the National Institutes of Health's Clinical and Translational Science Award (CTSA) recipients to improve their methods and processes in conducting clinical research. While CTSA recipient, New Jersey Alliance for Clinical and Translational Science (NJ ACTS), responded to this call to action with significant clinical research milestones, a comprehensive understanding of regulatory metrics during the COVID-19 pandemic is uncertain. The objective of this research is to identify, compare, and contrast metrics that illustrate the effectiveness of NJ ACTS's research mobilization efforts during COVID-19. Methods: Data were collected from the Institutional Review Board (IRB), the Clinical Research Units (CRUs), and the Office of Research and Sponsored Programs (ORSP). IRB data detailed the volume and types of protocols approved and turnaround time (TAT) for approval in 2020 vs. 2019. CRU data examined study metrics of adult and pediatric clinical trials across 2018-2020. ORSP data documented awards received in 2019 and 2020. Results: Analysis revealed a 95% increase in IRB-approved studies in 2020, with a significant decrease in TAT for COVID-19 studies. All CRUs observed a median 5.2-fold increase in the enrollment of adult and pediatric participants for COVID-19-related research. Study income was 106% and 196% greater than 2019 and 2018, respectively, with more than half funded through federal sponsors and 89% for COVID-19 trials. ORSP data revealed that 9% of awards and 26% of 2020 funding were COVID-19 studies. Conclusion: This study demonstrates that NJACTS effectively responded to challenges posed by the pandemic.

Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice.

Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH.

Medical student research exposure via a series of modular research programs.

BACKGROUND: The falling percentage of doctors of medicine applying for National Institute of Health-funded research grants is 1 indicator that physician-scientists are a disappearing breed. This is occurring at a time when increased translational, disease-oriented, patient-oriented, and clinical research are national goals. One of the keys to providing sufficient numbers of physician-scientists to support this goal is the active targeting of medical students. We hypothesize that an improved research program infrastructure and responsiveness to changing student needs will increase student participation in research-oriented electives. METHODS: We have developed a student research program consisting of 2 Students Interested in Research noncredit electives (lecture and laboratory based), summer fellowships, support for year-out fellowships, and a Distinction in Research program that spans undergraduate medical education. Student participation and short-term research outcomes from fall 2004 through spring 2008 are analyzed to examine program efficacy. RESULTS: Students involved in the early parts of the program initially experienced higher application and success rates for summer funding opportunities, but as the program has matured, these rates have fallen in line with the class average. Independently, students participating in later portions of the program increasingly submit or publish a first author paper and have taken a year off for research during medical school. Overlap of participation in the programs is generally smaller than expected. CONCLUSION: Although structured programs can provide step-wise research experiences of increasing intensity, students may not experience a training pipeline in which each stage relies on those before and after, and instead may sample an a la carte selection of research-based enrichment opportunities.

Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice.

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

Oxygen-sensing neurons in the central nervous system.

This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.

Heme oxygenase-1 and chronic hypoxia.

A myriad of changes are necessary to adapt to chronic hypoxemia. Key among these changes increases in arterial oxygen carrying capacity, ventilation and sympathetic activity. This requires the induction of several gene products many of which are regulated by the activity of HIF-1α, including HO-1. Induction of HO-1 during chronic hypoxia is necessary for the continued breakdown of heme for the enhanced production of hemoglobin and the increased respiratory and sympathetic responses. Several human HO-1 polymorphisms have been identified that can affect the expression or activity of HO-1. Associations between these polymorphisms and the prevalence of hypertension have recently been assessed in specific populations. There are major gaps in our understanding of the mechanisms of how HO-1 mediates changes in the activity of the hypoxia-sensitive chemosensors and whether HO-1 polymorphisms are an important factor in the integrated response to chronic hypoxia. Understanding how HO-1 mediates cardiorespiratory responses could provide important insights into clinical syndromes such as obstructive sleep apnea.

Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: a mechanism of possible relevance to the Restless Legs Syndrome (RLS) and Parkinson's disease.

Hypofunction of the endogenous opioid, dopamine and iron systems are implicated in the pathogenesis of Restless Legs Syndrome (RLS). Therefore, we probed the interrelationship of these 3 systems in an in vitro model. Cell cultures of the substantia nigra (SN) of Sprague-Dawley rats were established and the cells were determined to be primarily dopaminergic. The numbers of cells surviving under different concentrations of the iron chelator desferoxamine were reduced in a concentration and time dependent manner (p<0.01 at day 10, n=19). The cell death was determined to be apoptotic and DNA analysis revealed that 48-hour 100 µM desferoxamine exposure caused DNA fragmentation of the cells. Pre-administration of the δ-opioid peptide [D-Ala2, D-Leu5]Enkephalin (DADLE) significantly protected the SN cells from damage by iron deficiency (n=6, p<0.01). Our previous studies indicate that the DNA-damage induced apoptosis family gene P53 is activated in this model and that pre-exposure to DADLE prevents this activation. The implications of this model are that in RLS patients with iron deficiency, dopaminergic system dysfunction may result and an intact endogenous opioid system or opioid treatment may protect the dopamine system from dysfunction. Implications of this model for Parkinson's Disease are also briefly discussed.

Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons to hypoxia.

Heme oxygenase has been linked to the oxygen-sensing function of the carotid body, pulmonary vasculature, cerebral vasculature, and airway smooth muscle. We have shown previously that the cardiorespiratory regions of the rostral ventrolateral medulla are excited by local hypoxia and that heme oxygenase-2 (HO-2) is expressed in the hypoxia-chemosensitive regions of the rostral ventrolateral medulla (RVLM), the respiratory pre-Bötzinger complex, and C1 sympathoexcitatory region. To determine whether heme oxygenase is necessary for the hypoxic-excitation of dissociated RVLM neurons (P1) cultured on confluent medullary astrocytes (P5), we examined their electrophysiological responses to hypoxia (NaCN and low Po(2)) using the whole-cell perforated patch clamp technique before and after blocking heme oxygenase with tin protoporphyrin-IX (SnPP-IX). Following the electrophysiological recording, immunocytochemistry was performed on the recorded neuron to correlate the electrophysiological response to hypoxia with the expression of HO-2. We found that the responses to NaCN and hypoxia were similar. RVLM neurons responded to NaCN and low Po(2) with either depolarization or hyperpolarization and SnPP-IX blocked the depolarization response of hypoxia-excited neurons to both NaCN and low Po(2) but had no effect on the hyperpolarization response of hypoxia-depressed neurons. Consistent with this observation, HO-2 expression was present only in the hypoxia-excited neurons. We conclude that RVLM neurons are excited by hypoxia via a heme oxygenase-dependent mechanism.