Roles of Mechanosensitive Channels in Pressure Wave-Induced Retinal Damage
Abstract
Rationale: Blast-induced injury is primarily due to the pressurized airwave. Blasts may damage vision without causing damage to other organs, and the mechanism is unclear. There are no therapies currently used in humans to lessen the lingering and often severe symptoms. This study attempts to dissect the mechanism underlying the traumatic retinal injury (TRI) associated with blasts, advancing pioneering studies on pressure-related retinal disease and retinal mechanical sensitive ion channels (MSCs) from the PI and colleagues toward clinical translation. Per military studies, blast pressure of 20 psi caused fatalities of ~100%, and that of 3-5 psi caused widespread injuries and fatalities, demonstrating that moderate pressure levels are highly relevant to injuries in blast survivors. At the same time, blast exposure may be repetitive, but most studies have chosen single pressure wave greater than or equal to 20 psi. A few studies have shown retinal or brain injury by the pressure of ~4 psi and revealed repetitive blast exposure and oscillating pressure wave at 3-20 Hz as two new injury factors for TRI. The peripheral vision is usually more vulnerable to pressure than the central vision. The mechanism is unclear, and the vision loss remains untreatable. The peripheral vision is dominated by retinal rod-pathway neurons. We have recently observed pressure-evoked electric signals and the presence of MSCs in rod photoreceptors and rod bipolar cells (RBCs), including those passing potassium ions (termed K+-MSCs) and transient receptor potential channels (TRPs) that pass calcium more than sodium ions. MSC opening consumes ATPs, and high calcium is neurodegenerative. Yet, the role of MSCs in TRI has been unclear. Objectives: The study will determine: (1) The co-expression of K+-MSC and TRPs in rods, RBCs, and retinal ganglion cells (RGCs); (2) Pressure-caused degeneration of these neurons in the peripheral and central retina; (3) Pressure effect on the MSC opening in rods and signals that RBCs receive from rods and amacrine cells and output to RGCs; (4) Neuroprotective or neurogenerative roles with five experimental groups and more than four influencing factors, including administration of an energy provider, genetically suppressing the expression of a TRP and opening of a K+-MSC, and injection of a K+-MSC s activator with a TRP blocker. A train of pressure pulses of ~3-6 psi, 3-30 Hz, and pulse duration of 10 ms will be used to simulate repetitive blasts. Three specific aims are designed, with Aims 1-3 focusing on rods, RBCs, and RGCs, respectively. Aim 1a will quantify the relationship between MSC opening with the pressure amplitude and frequency, confirming the involvement of MSCs in the pressure response of mammalian rods. Aims 1b, 2b, and 3b will access the pressure-induced degeneration of rods, RBCs, and RGCs, respectively. Aim 2a will record electrical signals from RBCs to quantify the synaptic inputs and outputs. Aims 1a, 1b, 2a, 2b, and 3a will utilize the five experimental groups to screen novel neuroprotective and neurodegenerative factors. Aims 1c, 2c, and 3b will use wild-type and mutant animals to analyze the co-presence of K+-MSCs with TRPs to access their collaborative roles. Impact: (A) The data to be obtained will establish a novel TRP-mediated mechanism for TRI, filling the knowledge gap in retinal neuronal MSCs. (B) A balance between K+-MSCs and TRPs will be identified in individual retinal neurons, where K+-MSCs mediate hyperpolarizing currents to counterbalance excitatory currents mediated by TRPs, proving a mechanism essential for neurons to cope with pressure changes. (C) Military Service Members will immediately benefit from the finding of the neuroprotective effect of the energy provider and the K+-MSC’s activator (also an analgesic drug), which are medicines used for other conditions. Successful completion of this project will identify energy shortage, K+-MSCs, and TRPs as nov
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210741
Entities
People
- Jijie Pang
Organizations
- Baylor College of Medicine
- United States Army