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Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke

Award Number: R01NS069726
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The adult brain has a remarkable capacity to recover from focal ischemic stroke (FIS). Astrocytes are the most numerous and diverse glial cells in CNS and intimately interact with neurons to support and regulate their functions. After FIS, astrocytes in the PIR exhibit dynamic changes in morphology, proliferation and gene expression especially in the peri-infarct region (PIR). These astrocytes are called reactive astrocytes (RAs). However, whether and how reactive astrocytes (RAs) affect brain recovery after FIS in the context of astrocyte—neuron interactions largely remain unexplored. In our preliminary study, we found GDNF, a potent neurotrophic factor, is dramatically upregulated in the ischemic hemisphere and RAs after photothrombosis (PT)-induced FIS. Furthermore, we found that deletion of astrocytic GDNF reduces adult neurogenesis in normal brain, and increases brain infarction and attenuates cell proliferation in the PIR after PT. Based on these strong preliminary results, we hypothesize that RAs-derived GDNF plays an important role in neural regeneration and functional brain recovery after FIS. The prohect goal is to determine whether and how RAs- derived GDNF stimulates synaptic regeneration and remodeling of surviving neurons in the PIR and improves long-term stroke outcomes after FIS. To achieve this goal, we have developed interdisciplinary technologies including self-complementary adeno-associated virus (scAAV) vectors and Glast-CreERT2:GDNFf/f mice to specifically overexpress or delete GDNF in RAs during post FIS time, in vivo two photon (2-P) long-term microscopy, electrophysiology, immunocytochemistry, Western blot (WB) analysis, brain damage and neuronal death assays and behavioral tests. We propose three specific aims. In Aim 1, we will test the hypothesis that RAs-derived GDNF can enhance synaptogenesis to stimulate neural regeneration in the PIR after FIS. We will determine the effects of RAs-derived GDNF on the expression of neuronal proteins involving synaptic function and plasticity in the PIR; using TRAP (translating ribosome affinity purification) method we will further identify neuronal transcript changes at translational status in the PIR. In Aim 2, we will test the hypothesis that RAs- derived GDNF can promote structural and functional synaptic remodeling of surviving neurons in the PIR after FIS. Using in vivo long-term 2-P imaging we will determine the effect of RAs-derived GDNF on spine turnover (i.e., spine formation and elimination), glutamate release and Ca2+ signaling in the same dendrites of surviving neurons in the PIR. We will conduct patch-clamp recording on surviving neurons in the PIR to determine the effect of RAs-derived GDNF on functional synaptic plasticity. In Aim 3, we will test the hypothesis that astrocytic GDNF can improve long-term stroke outcomes. We will evaluate the effect of RAs-derived GDNF on long-term histological and behavioral outcomes. Our project will provide novel molecular, cellular and functional insights into the brain recovery processes after FIS in the context of glia-neuron interactions, reveal potential strategies for stroke therapy, and thus has both scientific and translational significances.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $351,064 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/14/2022	NON-COMPETING CONTINUATION	$351,064
														Subtotal = $351,064

Issue Date FY: 2021 ( Subtotal = $351,064 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/29/2021	NON-COMPETING CONTINUATION	$351,064
														Subtotal = $351,064

Issue Date FY: 2020 ( Subtotal = $351,064 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/20/2020	NON-COMPETING CONTINUATION	$351,064
														Subtotal = $351,064

Issue Date FY: 2019 ( Subtotal = $357,457 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/11/2019	NON-COMPETING CONTINUATION	$357,457
														Subtotal = $357,457

Issue Date FY: 2018 ( Subtotal = $365,130 )
2018	2018	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/3/2018	COMPETING CONTINUATION	$365,130
														Subtotal = $365,130

Issue Date FY: 2014 ( Subtotal = $309,949 )
2014	2014	CURATORS OF THE UNIVERSITY OF MISSOURI	5100 Rockhill Road	Kansas City	MO	64110	JACKSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/2/2014	NON-COMPETING CONTINUATION	$309,949
														Subtotal = $309,949

Issue Date FY: 2013 ( Subtotal = $302,450 )
2013	2013	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/21/2013	NON-COMPETING CONTINUATION	$20,372
2013	2013	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/26/2013	NON-COMPETING CONTINUATION	$282,078
														Subtotal = $302,450

Issue Date FY: 2012 ( Subtotal = $313,733 )
2012	2012	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/17/2012	NON-COMPETING CONTINUATION	$313,733
														Subtotal = $313,733

Issue Date FY: 2011 ( Subtotal = $314,071 )
2011	2011	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/6/2011	NON-COMPETING CONTINUATION	$25,638
2011	2011	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/19/2011	NON-COMPETING CONTINUATION	$288,433
														Subtotal = $314,071

Issue Date FY: 2010 ( Subtotal = $311,787 )
2010	2010	CURATORS OF THE UNIVERSITY OF MISSOURI	310 Jesse Hall	Columbia	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/12/2010	NEW	$311,787
														Subtotal = $311,787

Grand Total All Awards = $3,327,769

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Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke

Award Number: R01NS069726

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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