Mitochondrial Transplantation Strategies to Promote Recovery after Spinal Cord Injury

促进脊髓损伤后恢复的线粒体移植策略

基本信息

批准号：
9210134
负责人：
Alexander George Rabchevsky
金额：
$ 18.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210134
关键词：
Acute Allogenic Animals Antibodies Area Astrocytes Autologous Behavioral Bioenergetics Cell Culture Techniques Cells Chronic Complement Confocal Microscopy Data Dose Endothelial Cells Fixatives Fostering Frequencies Functional disorder Future Goals Hindlimb Histological Techniques Histology Homeostasis Image Immunohistochemistry Inflammation Injectable Injury Investigation Knowledge Label Leg Limb structure Locomotion Locomotor Recovery Measures Mediating Microglia Mission Mitochondria Modeling Multienzyme Complexes Muscle Nervous System Trauma Neurons Oligodendroglia Outer Mitochondrial Membrane Oxidative Stress Oxygen Consumption PC12 Cells Process Rattus Recovery Recovery of Function Research Research Proposals Respiration Rodent Seminal Series Site Soleus Muscle Source Spinal Spinal Cord Spinal Cord Contusions Spinal cord injury Subcellular Fractions Techniques Testing Therapeutic Time Tissues Transgenic Organisms Transplantation Traumatic injury United States National Institutes of Health base cell type clinically relevant comparative design dosage experimental study gait examination improved inflammatory marker injured innovation insight muscle transplantation nano neuroprotection novel therapeutic intervention novel therapeutics prevent public health relevance response stem targeted treatment trend

项目摘要

DESCRIPTION (provided by applicant): The current proposal is designed to develop of a new research area that is aimed at transplanting mitochondria into the injured rodent spinal cord as a therapeutic strategy following traumatic spinal cord injury (SCI). We and others have found that maintaining normal mitochondrial bioenergetics after contusion SCI fosters both neuroprotection and functional recovery. However, no studies have examined the effects of transplanting exogenous mitochondria into spinal cord tissue after injury in an attempt to normalize overall cellular bioenergetics and spare adjacent host tissues. Accordingly, this new line of investigations will test, ultimately, whether transplanting exogenous healthy mitochondria into the injured spinal cord promotes functional neuroprotection. Using a rat model of contusion SCI, we have preliminary data showing that allogeneic transgenically-labeled (turboGFP) mitochondria derived from PC12 cells microinjected around the injury site maintain overall cellular bioenergetics assessed 24 hrs later. Moreover, using confocal microscopy to evaluate specific antibodies to both inner and outer mitochondrial membranes, we have preliminary evidence that grafted turboGFP mitochondria integrate within naïve and injured spinal cord tissues. Based on these seminal findings, we propose to conduct a series of transplantation strategies to deliver mitochondria around the injury sites. The ultimate goal is to identify a potential autologous cell source of mitochondria (i.e., leg muscle) to prevent secondary tissue injury that is mediated, in large part, by mitochondrial loss and dysfunction. In summary, Aim 1a will comparatively employ a dose-response approach to assess whether transplanted MitoTracker Red-labeled mitochondria isolated from muscles are equally effective as allogeneic turboGFP mitochondria on cellular bioenergetics and the extent of inflammation following acute contusion SCI. Aim 1b will then assess comparatively the frequency and distribution of labeled mitochondria incorporated into host cells over the first week post-injury. Finally, Aim 2 will establish whether transplantation of muscle-derived mitochondria increases long-term tissue sparing and recovery of hindlimb locomotion following SCI. This project has translational potential wherein mitochondria, notably autologous, can be transplanted around the injury site to spare penumbral tissues. Based on the collective expertise of the PI in cellular transplantation into injured spinal cord tissue and both Co-Is in bioenergetic assessments and mitochondrial-targeted therapeutics for neurotrauma, along with our preliminary feasibility data, there are no foreseen technical obstacles to successfully carry out this project. Notably, future experiments stemming from the results of the current proposal will be designed to test delayed grafting paradigms to extend a more clinically relevant therapeutic time window for transplantation of mitochondria to promote functional recovery in more chronic SCI models.