Gordon S. Mitchell

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Neuroplasticity and Neural Repair

Active NIH awards

• Microglial regulation of intermittent hypoxia induced phrenic motor plasticity

  2R01HL149800-05A1

  NHLBI · FY 2025 · $1.5M

  ABSTRACT A well-studied model of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output following moderate acute intermittent hypoxia (mAIH). Over 2 decades, we developed a nuanced understanding of intra-cellular mechanisms giving rise to pLTF, and factors regulating its expression in the rest/light phase. With mAIH, serotonin-driven pLTF is constrained by modest adenosine 2A (A2A) receptor activation. When extracellular adenosine levels are high, greater A2A receptor activation initiates an alternate adenosine-dependent mechanism of plasticity. Although the serotonin driving plasticity arises from raphe serotonergic neurons, the cellular source of adenosine was unknown. Thus, in the first 4 years of this grant, we asked the question: what is the source of hypoxia-evoked adenosine? We developed an inter-cellular model whereby phrenic motor neuron to microglia signaling evokes spinal adenosine formation and regulates pLTF. During hypoxia, phrenic motor neurons release Fractalkine (Fkn) and activate receptors on the lone CNS cell- type expressing Fkn receptors—microglia. Microglia respond by converting extracellular ATP to adenosine, restraining serotonin-driven pLTF. These experiments were performed during the daily rest/light phase; our discovery that mAIH delivered in the active (vs rest) phase profoundly impacts the mechanism driving pLTF due to diurnal shifts in basal adenosine levels lead us to realize we must update our model to account for rest/active phase differences. Two fundamental hypotheses guide this proposal: 1) shifts in microglial state across the rest/active cycle alter phrenic motor neuron/microglia interactions and, thus, mAIH-induced pLTF; and 2) microglial (and pLTF) responses to pro-inflammatory stimuli reverse in the active/dark phase. Using a multi-disciplinary approach, we will interrogate a revised inter-cellular model by testing 5 hypotheses: 1) Phrenic motor neuron-microglia fractalkine signaling inhibits pLTF less in the active/dark phase; even though 2) Fkn receptor activation evokes greater active phase spinal adenosine formation; 3) Microglial expression of key molecules for adenosine formation increases in the active (dark) phase; 4) Unlike the rest/light phase, mild systemic inflammation has minimal impact, or even enhances active phase pLTF; and 5) Due to differences in microglial reactivity, ventilatory LTF exhibits sexual dimorphism during the rest (not active) phase. We know little concerning the impact of “biological clocks” in any aspect of ventilatory control, let alone respiratory plasticity. Thus, we will expand on our discovery that time-of-day has powerful effects on AIH-induced pLTF by considering the complex rest/active phase effects on phrenic motor neuron/microglia interactions. Regardless of outcome, these studies will greatly advance our understanding of diurnal rhythms in respiratory plasticity and accelerate ongoing efforts to develop AIH as a therapeutic modality to treat devastating human clinical disorders that compromise breathing, threatening life itself. Greater understanding of diurnal rhythms is sorely needed since nocturnal rodents and diurnal humans are typically studied in opposite phases of the rest/active cycle.

• Breathing Research and Therapeutics (BREATHE)

  5T32HL134621-09

  NHLBI · FY 2025 · $333K

  We propose renewal of the Breathing Research and Therapeutics (BREATHE) Training Program at the University of Florida (UF). This combined predoctoral and postdoctoral training program, which began in 2017, is focused on the respiratory neuromuscular system, emphasizing discovery of new knowledge and its translation to severe clinical disorders that compromise breathing capacity, stability and airway defense. In just over 4 years, with a “ramp-up” of 2 years, we established an internationally known training program with a “unique focus, unlike any other” (quote from anonymous NIH reviewer); we are unaware of any other T32 with a similar concentration on breathing and airway defense in traumatic, ischemic, infectious or degenerative clinical disorders. Nine predoctoral and 7 postdoctoral trainees have been funded through the BREATHE training program; all graduates have continued in academic, biomedical or research positions. In this renewal, we will continue building and refining this unique program, with the goal of training the next generation of scientists devoted to preserving and restoring breathing and airway defense in clinical disorders that most often end life by respiratory failure. Our intent is to establish a cohort of respiratory scientists capable of engaging in basic discovery and clinical/translational research. BREATHE emphasizes training in respiratory neural and muscle plasticity, and development of new therapeutic strategies to treat patients with compromised breathing capacity, stability and/or airway defense. Our objectives are: 1) recruit a cohort of high-quality basic science and clinical predoctoral and postdoctoral candidates with an interest in breathing research and therapeutics, and the potential for long-term success as independent investigators; 2) implement a carefully designed training program that provides predoctoral and postdoctoral trainees with solid foundations in respiratory biology, airway defense and translational research, and the technical, analytical and professional skills necessary for productive research careers; and 3) foster a collaborative research environment conducive to preparing scientists for successful careers in interdisciplinary research. The UF environment includes collaborative faculty mentors with varied yet complementary expertise, state-of-the-art facilities, ongoing translational research partnerships and a rich menu of career development opportunities. Our renewal application builds on proven elements, with an emphasis on being responsive to the rapidly changing landscape of respiratory research.