Unesterified cholesterol controls the fluidity, permeability and electrical properties of eukaryotic cell mem- branes. Consequently, cholesterol levels in the retina and the brain are tightly regulated whereas depleti...Unesterified cholesterol controls the fluidity, permeability and electrical properties of eukaryotic cell mem- branes. Consequently, cholesterol levels in the retina and the brain are tightly regulated whereas depletion or oversupply caused by diet or heredity contribute to neurodegenerative diseases and vision loss. Astrog- lia play a central role in the biosynthesis, uptake and transport of cholesterol and also drive inflammatory signaling under hypercholesterolemic conditions associated with high-fat diet （diabetes） and neurodegen- erative disease. A growing body of evidence shows that unesterified membrane cholesterol modulates the ability of glia to sense and transduce ambient information. Cholesterol-dependence of Mfiller glia - which function as retinal sentinels for metabolic, mechanical, osmotic and inflammatory signals - is mediated in part by transient receptor potential V4 （TRPV4） channels. Cholesterol supplementation facilitates, where- as depletion suppresses, TRPV4-mediated transduction of temperature and lipid agonists in Mfiller cells. Acute effects of cholesterol supplementation/depletion on plasma membrane ion channels and calcium ho- meostasis differ markedly from the effects of chronic dyslipidemia, possibly due to differential modulation of modality-dependent energy barriers associated with the functionality of polymodal channels embedded within lipid rafts. Understanding of cholesterol-dependence of TRP channels is thus providing insight into dyslipidemic pathologies associated with diabetic retinopathy, glaucoma and macular degeneration.展开更多
The study of respiratory plasticity in animal models spans decades.At the bench,researchers use an array of techniques aimed at harnessing the power of plasticity within the central nervous system to restore respirati...The study of respiratory plasticity in animal models spans decades.At the bench,researchers use an array of techniques aimed at harnessing the power of plasticity within the central nervous system to restore respiration following spinal cord injury.This field of research is highly clinically relevant.People living with cervical spinal cord injury at or above the level of the phrenic motoneuron pool at spinal levels C3-C5 typically have significant impairments in breathing which may require assisted ventilation.Those who are ventilator dependent are at an increased risk of ventilator-associated co-morbidities and have a drastically reduced life expectancy.Pre-clinical research examining respiratory plasticity in animal models has laid the groundwork for clinical trials.Despite how widely researched this injury is in animal models,relatively few treatments have broken through the preclinical barrier.The three goals of this present review are to define plasticity as it pertains to respiratory function post-spinal cord injury,discuss plasticity models of spinal cord injury used in research,and explore the shift from preclinical to clinical research.By investigating current targets of respiratory plasticity research,we hope to illuminate preclinical work that can influence future clinical investigations and the advancement of treatments for spinal cord injury.展开更多
基金supported by the NIH(R01EY022076,R01EY027920P30EY014800)+1 种基金the Willard Eccles Foundation,Glaucoma Research Foundationthe Diabetes and Metabolism Center at the University of Utah and unrestricted support from Research to Prevent Blindness to the Moran Eye Institute at the University of Utah,USA
文摘Unesterified cholesterol controls the fluidity, permeability and electrical properties of eukaryotic cell mem- branes. Consequently, cholesterol levels in the retina and the brain are tightly regulated whereas depletion or oversupply caused by diet or heredity contribute to neurodegenerative diseases and vision loss. Astrog- lia play a central role in the biosynthesis, uptake and transport of cholesterol and also drive inflammatory signaling under hypercholesterolemic conditions associated with high-fat diet （diabetes） and neurodegen- erative disease. A growing body of evidence shows that unesterified membrane cholesterol modulates the ability of glia to sense and transduce ambient information. Cholesterol-dependence of Mfiller glia - which function as retinal sentinels for metabolic, mechanical, osmotic and inflammatory signals - is mediated in part by transient receptor potential V4 （TRPV4） channels. Cholesterol supplementation facilitates, where- as depletion suppresses, TRPV4-mediated transduction of temperature and lipid agonists in Mfiller cells. Acute effects of cholesterol supplementation/depletion on plasma membrane ion channels and calcium ho- meostasis differ markedly from the effects of chronic dyslipidemia, possibly due to differential modulation of modality-dependent energy barriers associated with the functionality of polymodal channels embedded within lipid rafts. Understanding of cholesterol-dependence of TRP channels is thus providing insight into dyslipidemic pathologies associated with diabetic retinopathy, glaucoma and macular degeneration.
基金supported by funds awarded from the National Institutes of Health R01 NS104291Wings for Life(to MAL)the Lisa Dean Moseley Foundation(to LVZ).
文摘The study of respiratory plasticity in animal models spans decades.At the bench,researchers use an array of techniques aimed at harnessing the power of plasticity within the central nervous system to restore respiration following spinal cord injury.This field of research is highly clinically relevant.People living with cervical spinal cord injury at or above the level of the phrenic motoneuron pool at spinal levels C3-C5 typically have significant impairments in breathing which may require assisted ventilation.Those who are ventilator dependent are at an increased risk of ventilator-associated co-morbidities and have a drastically reduced life expectancy.Pre-clinical research examining respiratory plasticity in animal models has laid the groundwork for clinical trials.Despite how widely researched this injury is in animal models,relatively few treatments have broken through the preclinical barrier.The three goals of this present review are to define plasticity as it pertains to respiratory function post-spinal cord injury,discuss plasticity models of spinal cord injury used in research,and explore the shift from preclinical to clinical research.By investigating current targets of respiratory plasticity research,we hope to illuminate preclinical work that can influence future clinical investigations and the advancement of treatments for spinal cord injury.
