Exosomes, small lipid microvesicles (30-150 nm), are active biological containers, which transport regulatory genes and proteins between cells and form a major biological communication conduit, facilitating a plethora of biological responses. The regulatory molecules contained in the exosomes include microRNAs (miRNAs), short (22-25 nt) non-coding RNAs which regulate gene translation and play primary roles in mediating a vast range of biological functions. In this proposal, based on strong preliminary data, we propose to manufacture a distinct exosome population which contains increased levels of the miR-17-92 cluster as a proof-of-principle and a mechanistic demonstration of a new method of treating stroke and possibly other neurological diseases and injury. We test the premise, that by modulating their miRNA content, exosomes can be designed to enhance plasticity of axons and thereby further promote neurological recovery post stroke. Success of this novel approach may lead to a new designer-based paradigm for the treatment of stroke and neurological disease. The following Specific Aims and associated Hypotheses are proposed:
Specific Aim 1 : To employ exosomes derived from multipotent mesenchymal stromal cells (MSCs) to treat stroke in order to enhance neurovascular remodeling and thereby, functional recovery post stroke. Hypothesis: Exosomes, derived from MSCs when administered to rats after stroke promote neurovascular remodeling which improves functional outcome.
Specific Aim 2 : To alter specific miRNAs contained within exosomes generated by MSCs as a means to enhance axonal plasticity and neurological recovery post stroke. Hypothesis: Administration of exosomes with increased miR-17-92 cluster to rats post stroke promotes axonal remodeling and enhances functional outcome. There are multiple layers of innovation in our application: we generate biological exosome carriers tailored for specific miRNAs; we use these exosomes to treat stroke, without the administration of exogenous cells; we employ electrophysiological methods, laser capture, fiber track tracing, a battery of neurological tests, and an array of novel approaches, e.g. microfluidic chambers, and ex vivo slice cultures, to mechanistically determine the molecular pathways of the target exosomes which mediate axonal outgrowth. Development of this designer exosome-based therapy, also serves as a prototype for capitalizing on the characteristics of exosomes to transport specific miRNAs and for the manufacture of designer exosomes. Developing a therapy for stroke that is exosome-based, opens up a wide variety of means to deliver targeted regulatory genes to enhance multifaceted aspects of central nervous system (CNS) plasticity and to amplify neurological recovery for neural injury and neurodegenerative diseases.

Public Health Relevance

We test the premise that by modulating the microRNA content of exosomes, they can be designed to enhance plasticity of axons and thereby further promote neurological recovery post stroke. Success of this novel approach may lead to a new designer-based paradigm for the treatment of stroke, neural injury and neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088656-02
Application #
8996733
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2015-02-01
Project End
2019-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Venkat, Poornima; Chopp, Michael; Chen, Jieli (2016) New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain. Croat Med J 57:223-8
Zhang, Zhenggang; Chopp, Michael (2016) Neural Stem Cells and Ischemic Brain. J Stroke 18:267-272
Zhang, Yanlu; Chopp, Michael; Zhang, Zheng Gang et al. (2016) Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int :
Liu, Xian Shuang; Fan, Bao Yan; Pan, Wan Long et al. (2016) Identification of miRNomes associated with adult neurogenesis after stroke using Argonaute 2-based RNA sequencing. RNA Biol :1-12
Zhang, Zheng Gang; Chopp, Michael (2016) Exosomes in stroke pathogenesis and therapy. J Clin Invest 126:1190-7
Zhang, Yi; Chopp, Michael; Liu, Xian Shuang et al. (2016) Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons. Mol Neurobiol :
Liu, Xian Shuang; Chopp, Michael; Pan, Wan Long et al. (2016) MicroRNA-146a Promotes Oligodendrogenesis in Stroke. Mol Neurobiol :
Liu, Zhongwu; Chopp, Michael (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103-20
Xin, Hongqi; Wang, Fengjie; Li, Yanfeng et al. (2016) Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b(-)overexpressed multipotent mesenchymal stromal c Cell Transplant :
Cui, Xu; Chopp, Michael; Zacharek, Alex et al. (2016) D-4F Decreases White Matter Damage After Stroke in Mice. Stroke 47:214-20

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