2010 — 2017 |
Mantilla, Carlos B. Sieck, Gary C. [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Recovery of Respiratory Function After Spinal Cord Injury
DESCRIPTION (provided by applicant): The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of respiratory function following cervical spinal cord injury (SCI). There are about 12,000 new cases of SCI in the United States each year, with nearly 500,000 people affected. Most SCI's are incomplete with some sparing of spinal cord pathways. The number of injuries involving the cervical spinal cord is increasing, with resulting impairments of rhythmic phrenic nerve activity and paralysis of the diaphragm muscle. Inability to generate expulsive behaviors as well as long-term mechanical ventilation needed to support such SCI patients is associated with elevated infectious, morbidity and mortality rates. In recent studies supported by this grant, we found that the neurotrophin brain-derived neurotrophic factor (BDNF) acting through the full-length high affinity tropomyosin related kinase receptor subtype B (TrkB.FL) plays an important role in neuroplasticity and recovery of phrenic activity following SCI. This proposal will exploit a multi-pronged approach to gain mechanistic insight into the effects of BDNF/TrkB.FL signaling on: 1) strengthening of spared synaptic inputs to phrenic motoneurons, and 2) enhancing motoneuron survival post-SCI. Our working hypothesis is that increasing BDNF/TrkB.FL signaling in phrenic motoneurons enhances functional recovery of rhythmic phrenic activity after cervical SCI. Three complementary models of cervical SCI that differentially impact respiratory function will be used in combination with targeted intrapleural AAV-mediated delivery of TrkB.FL to phrenic motoneurons, localized transplantation of adult-derived mesenchymal stem cells engineered to release BDNF and a chemical-genetic approach using a TrkB knock-in mouse that permits rapid and selective inhibition of TrkB kinase activity in gain-of-function/loss-of-function study design. Phrenic motoneuron expression of excitatory glutamate and serotonin receptors correlates with the time course of functional recovery after SCI, and thus we hypothesize that BDNF/TrkB.FL acts on phrenic motoneurons to enhance recovery of rhythmic phrenic activity via expression of specific glutamate and serotonin receptor subtypes. Three specific aims are proposed: 1) To determine whether functional recovery of rhythmic phenic activity after SH is enhanced by targeting increased BDNF/TrkB.FL signaling to phrenic motoneurons; 2) To determine the role of glutamatergic and serotonergic neurotransmission in the BDNF/TrkB.FL mediated recovery of rhythmic phrenic activity after SH; and 3) To determine the role of enhanced phrenic motoneuron BDNF/TrkB.FL signaling on motoneuron survival and functional recovery following mid-cervical contusion injury. We will assess phrenic responses across a range of motor behaviors to maximize functional gains associated with recovery. Our long-term goal is to develop an effective, targeted therapy to increase BDNF/TrkB.FL signaling in phrenic motoneurons to strengthen spared synaptic inputs to phrenic motoneurons and promote motoneuron survival, thereby enhancing functional recovery following SCI.
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0.954 |
2013 — 2020 |
Mantilla, Carlos B. Sieck, Gary C. [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Respiratory Control in Old Age
DESCRIPTION (provided by applicant): There is substantial evidence that old age is associated with an increased incidence of respiratory complications that result from an inability to perform expulsive non-ventilatory behaviors such as coughing and sneezing. The proposed studies focus on the perfect storm condition related to old age, where we believe that sarcopenia (diaphragm muscle (DIAm) fiber atrophy and decreased specific force) together with increased neuromuscular transmission failure reduce the ability of the DIAm to generate force, and thus transdiaphragmatic pressure (Pdi), while at the same time the respiratory system mechanics are stiffening thereby increasing the load against which the DIAm must contract. The DIAm must accomplish a range of behaviors from resting breathing to expulsive behaviors such as coughing and sneezing. In the elderly, a deficit in the ability to perform expulsive, high-intensity, non-ventilatory behaviors likely contributes to increased risk for infections and respiratory failure. Our working hypothesis is that age-related sarcopenia and neuromuscular transmission failure reduce maximum DIAm force-generating capacity, impairing the ability of the elderly to perform non-ventilatory behaviors involved in airway clearance. The proposed research will determine the role of trophic influences exerted by brain-derived neurotrophic factor (BDNF) acting through tropomyosin related kinase receptor (TrkB) and neuregulin-1 (NRG-1) acting through ErbB receptors via mTOR activation on the age-related changes in DIAm innervation and sarcopenia. We hypothesize that trophic influences exerted by BDNF/TrkB and NRG-1/ErbB/mTOR signaling can be used therapeutically to mitigate aging-related DIAm neuromuscular transmission failure and sarcopenia, and the associated impairment of non-ventilatory behaviors. We propose the following three specific aims to address these hypotheses: 1) To determine the functional impact of old age on respiratory mechanics; 2) To determine the role of BDNF/TrkB signaling on the age-related changes in DIAm innervation; and 3) To determine the role of NRG-1/ErbB/mTOR signaling in age- related DIAm sarcopenia. The results of the proposed studies will provide new and fundamental knowledge of changes in the respiratory system in old age, and thus permit the development of novel therapies with broad application in respiratory and neuromuscular diseases. The greater incidence of chronic diseases associated with the aging of our population demands concerted efforts to improve the wellness of the elderly.
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0.954 |
2017 — 2021 |
Mantilla, Carlos B Sieck, Gary C. (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Age-Related Susceptibility of Nmj Function
ABSTRACT The goal of this application is to determine the role of trophic interactions in the susceptibility (or resilience) to the effects of aging on the neuromuscular system. Age-related neuromuscular dysfunction is an important determinant of overall health, limiting independence, increasing frailty and predisposing individuals to age- related co-morbidities and mortality. Interactions between motoneurons and the muscle fibers they innervate determine muscle fiber properties and have a significant impact on muscle function throughout the lifespan. Motoneuron-muscle fiber interactions are likely exerted via trophic factors that vary across muscle groups. Brain-derived neurotrophic factor (BDNF) acting via its high-affinity receptor tropomyosin related kinase receptor (TrkB) has a known role in the maintenance of the adult NMJ. However, the role of BDNF/TrkB signaling in old age is not presently understood. Exciting recent studies show that inhibition of TrkB kinase activity exerts deleterious effects on neuromuscular transmission that vary across age groups, replicating the effects of old age at young NMJs. The current proposal will use a combination of highly-innovative methods to explore mechanistically the role of disrupted trophic factor signaling at the NMJ in old age. Our working hypothesis is that susceptibility to age-related neuromuscular dysfunction depends on motoneuron-muscle fiber trophic influences exerted by BDNF/TrkB signaling at the NMJ (aim 1) and motoneuron (aim 2). Furthermore, trophic factors can determine susceptibility to neuromuscular damage resulting from autophagy imbalance causing accumulation of protein aggregates and degeneration in old age. Two specific aims are proposed: Specific Aim 1) To determine the cellular (trophic factor dependent) mechanisms underlying susceptibility to neuromuscular dysfunction in old age. Specific Aim 2) To determine the molecular (trophic factor dependent) mechanisms underlying age-related effects at motoneurons. These results constitute the necessary foundation for the development of targeted therapies to mitigate aging effects on neuromuscular performance and increase the health span in the aging population with therapies initiated later in life to combat frailty and disability.
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0.954 |
2019 — 2021 |
Mantilla, Carlos B Sieck, Gary C. [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Enhancing Respiratory Motor Function After Spinal Cord Injury
ABSTRACT The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of ventilatory- related diaphragm muscle (DIAm) activity following cervical spinal cord injury. There are nearly 17,000 new cases of spinal cord injury in the United States each year, with around 282,000 people affected. The majority of these injuries involve the cervical spinal cord and result in significant impairment of ventilatory-related DIAm activity and an inability to maintain adequate ventilation. Long-term dependence on mechanical ventilation is associated with significant morbidity and mortality. Thus, enhancing recovery of ventilatory-related DIAm activity following cervical spinal cord injury is highly significant. Upper-cervical (C1-C3) spinal cord injury disrupts direct excitatory descending bulbospinal glutamatergic (Glu) input to phrenic motor neurons (PhMNs). Importantly, most spinal cord injuries are incomplete, thus spared descending pathways to PhMNs are an extant substrate for neuroplasticity to restore DIAm activity, either by increasing excitatory (Glu) nerve terminal density and/or by altering postsynaptic Glu receptor (NMDA NR1) expression. In the proposed studies, we will employ a well-established C2 spinal hemisection (C2SH) model of incomplete spinal cord injury in rats, in which spontaneous recovery of ventilatory-related DIAm activity occurs in a BDNF/TrkB signaling-dependent fashion. Previously, we found that C2SH impairs ventilatory-related DIAm behaviors, which require recruitment of smaller (more excitable) PhMNs comprising fatigue resistant motor units. These ventilatory-related behaviors only partially recover over time, whereas, surprisingly, there is near full recovery of higher force airway clearance behaviors, which require recruitment of larger (less excitable) PhMNs comprising more fatigable motor units. The overall hypothesis of the proposed research is that the mechanisms underlying neuroplasticity and recovery of ventilatory-related DIAm activity after C2SH depend on PhMN size (more pronounced in smaller PhMNs), are mediated by NMDA Glu neurotransmission, and are promoted by BDNF/TrkB signaling. Three specific aims are proposed: 1) To determine the effect of BDNF/TrkB signaling on Glu presynaptic terminal density at PhMNs of differing size after C2SH; 2) To determine the effect of BDNF/TrkB signaling on NMDAR expression at PhMNs of differing size after C2SH; and 3) To determine whether NMDARs underlie the effects of BDNF/TrkB signaling on recovery of ventilatory-related DIAm activity after C2SH. The results of the proposed studies will guide development of effective therapeutic approaches to enhance recovery of respiratory function in patients with incomplete spinal cord injury.
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0.954 |