Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury

Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury

Bibliographic Details
Main Author: Paleo, Brian J.
Language:English
Published: The Ohio State University / OhioLINK 2020
Subjects:
Physiology
Neurosciences
MG53
membrane repair
TRIM2
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1595504131615976
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1595504131615976
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Physiology
Neurosciences
MG53
membrane repair
TRIM2
spellingShingle Physiology
Neurosciences
MG53
membrane repair
TRIM2
Paleo, Brian J.
Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
author Paleo, Brian J.
author_facet Paleo, Brian J.
author_sort Paleo, Brian J.
title Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
title_short Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
title_full Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
title_fullStr Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
title_full_unstemmed Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury
title_sort demonstrating the importance of membrane repair in response to disease and injury
publisher The Ohio State University / OhioLINK
publishDate 2020
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1595504131615976
work_keys_str_mv AT paleobrianj demonstratingtheimportanceofmembranerepairinresponsetodiseaseandinjury
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15955041316159762021-09-02T05:10:39Z Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury Paleo, Brian J. Physiology Neurosciences MG53 membrane repair TRIM2 Most cells in the human body have the capacity to reseal their cellular membranes following disruption of the lipid bilayer. This membrane repair response involves a coordinated chain of events that are essential to maintain cellular homeostasis and prevent cell death. Membrane repair initially emerged as an important field in skeletal muscle physiology, however as the field continues to mature the importance of membrane repair has been noted in many cell types and in the context of injuries related to bacterial toxins, ischemic events and traumatic injury. As the field begins to expand, it is important to understand the value of membrane repair in the tissue studied and if proteins known to be involved in membrane repair appear in specific tissues. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in striated muscle. In an effort to demonstrate the value of both MG53/TRIM72 and membrane repair in Duchenne muscular dystrophy (DMD), I studied the effects of genetic knock out of MG53/TRIM72 in the mdx mouse model of DMD. We observed muscle pathology consistent with the mdx mouse following the initial phase of pathology at 6 weeks of age. However, aging of the mice and resulting accumulation of repeated bouts of injury due to the lack of dystrophin protein led to robust fibrosis throughout skeletal and cardiac muscles.To expand the knowledge of membrane repair in tissues other than skeletal muscle we investigated if increasing membrane repair can have protective effects in the peripheral nervous system. Since many neurons are terminally differentiated, increasing cell survival following injury may minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase the membrane repair capacity of various cell types both in vitro and in vivo. Thus, we assessed the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in cultured cells and a mouse model of peripheral nerve injury. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.The previous study has identified the value of membrane repair in the nervous system, but identifying potential therapeutic proteins involved in membrane repair can provide targeted treatment for diseases that involve cell membrane injuries. We have previously shown that TRIM72/MG53 can increase plasma membrane repair in skeletal and cardiac muscle as well as non-muscle cell types where it is not usually expressed. This observation led us to screen for novel TRIM family proteins that may be able to mediate membrane repair in neuronal cells. We found that TRIM2 transfected cells show an increased capacity for membrane resealing following multi-photon laser injury, while knock down of TRIM2 decreases membrane repair. Because TRIM2 is highly expressed in the nervous system and was previously shown to regulate neurofilaments (NFL) we tested if TRIM2 protects against membrane damage in neurons through regulation of ubiquitination of NFLs and if disruption of TRIM2 or NFL leads to compromised membrane repair or neuronal cell death. Using confocal microscopy, TRIM2 and NFL were not observed to co-localize and immunoprecipitation only revealed an interaction when the two proteins were overexpressed. Additionally, knockout of NFL in primary neurons did not affect the ability of the cells to repair their membranes. The available data suggest that TRIM2 must use an alternative mechanism to mediate membrane repair in neurons.Overall, these studies demonstrate the importance of membrane repair in both skeletal muscle, cardiac muscle and nervous tissue. Future studies of membrane repair will increase the understanding of this essential process and establish that increasing membrane repair is a valuable target for therapeutic treatment. 2020-11-13 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1595504131615976 http://rave.ohiolink.edu/etdc/view?acc_num=osu1595504131615976 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.

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