All central nervous system (CNS) insults including trauma, infection, ischemia and degenerative disease trigger changes in astroglia known as reactive astrogliosis. The roles of reactive astroglia are not well established. Astroglia stimulated in vitro can produce a wide variety of molecules including both pro- and anti-inflammatory regulators, as well as cytotoxic and neuroprotective molecules. Accordingly, both harmful and beneficial effects have been attributed to reactive astrocytes. Our central hypothesis is that during the response to CNS insults, reactive astrocytes can exert effects that may be either beneficial or detrimental to clinical outcome in a manner that is context dependent and is regulated by specific inter- and intra-cellular signaling mechanisms. The signaling mechanisms that regulate activities implemented by reactive astrocytes in response to specific situations in vivo are not well understood. Our previous work used a transgenic mouse model to ablate reactive astrocytes and showed that these cells play pivotal roles in restricting inflammation and protecting tissue after brain or spinal cord injury in vivo. Our next goal is to identify molecular mechanisms that regulate specific activities of reactive astrocytes. To do so we have developed conditional gene deletion or knockout technology (CKO) for astrocytes using the Cre/loxP system under regulation of the mouse GFAP promoter in transgenic mice. Here we propose to determine the effects of selectively deleting STAT3, an intracellular signal transducer that has been implicated as a regulator of reactive astrogliosis. We will study spinal cord injury (SCI) and in vitro preparations using a combination of quantitative morphological and biochemical analyses. Our preliminary data show that mice with astroglial STAT3-CKO have CNS of normal size and cytology, and that astrocytes are generated in normal numbers. After SCI, reactive astrogliosis is attenuated and scar formation is disrupted in mice with astroglial STAT3- CKO. This proposal builds on our preliminary findings by investigating three specific aims that will determine the effects of astroglial STAT3-CKO: (1) on quantitative measures of astrocyte reactivity and scar formation after SCI in vivo and on various regulatory signaling pathways in vitro;(2) on inflammation, lesion size and short-term motor behavior after SCI in vivo, and on astrocyte expression in vitro of molecules that influence inflammation and cytotoxicity;and (3) on axon regeneration, inflammation and long-term motor behavior after SCI in vivo, and on the production in vivo and in vitro of molecules that inhibit both axon regeneration and inflammatory cell migration. The findings will provide fundamental information about signaling mechanisms that regulate astrogliosis after SCI. Such mechanistic information is essential for understanding the cellular and molecular interactions that determine functional outcome after SCI, and will help to identify key pathways and molecules that warrant targeting for potential therapeutic manipulation.

Public Health Relevance

Spinal cord injury has devastating consequences and little or no treatment options. Scar formation by reactive astrocytes is a prominent feature of spinal cord injury, and both harmful and beneficial effects have been attributed to reactive astrocytes. The work proposed here will benefit public health by identifying molecular signaling mechanisms that regulate specific functions of reactive astrocytes after spinal cord injury and can be targeted for therapeutic manipulation to improve outcome.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-J (05))
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Kleitman, Naomi
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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O'Shea, Timothy M; Burda, Joshua E; Sofroniew, Michael V (2017) Cell biology of spinal cord injury and repair. J Clin Invest 127:3259-3270
Levine, Jaclynn; Kwon, Eunice; Paez, Pablo et al. (2016) Traumatically injured astrocytes release a proteomic signature modulated by STAT3-dependent cell survival. Glia 64:668-94
Anderson, Mark A; Burda, Joshua E; Ren, Yilong et al. (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195-200
Burda, Joshua E; Bernstein, Alexander M; Sofroniew, Michael V (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275 Pt 3:305-315
Sofroniew, Michael V (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249-63
Zhang, Shanshan; Alvarez, Daniel J; Sofroniew, Michael V et al. (2015) Design and synthesis of nonionic copolypeptide hydrogels with reversible thermoresponsive and tunable physical properties. Biomacromolecules 16:1331-40
Khakh, Baljit S; Sofroniew, Michael V (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942-52
López-Valdés, Héctor E; Clarkson, Andrew N; Ao, Yan et al. (2014) Memantine enhances recovery from stroke. Stroke 45:2093-2100
Sofroniew, Michael V (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20:160-72
Anderson, Mark A; Ao, Yan; Sofroniew, Michael V (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565:23-9

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