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The role TGF-beta Signaling pathway in microglia and astrocytes homeostasis and cellular interactions

Award Number: R01NS125074
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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The role TGF-beta Signaling pathway in microglia and astrocytes homeostasis and cellular interactions - Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Recently it has been recognized that ischemic stroke elicits a strong neuroinflammatory response characterized by massive microglia and astrocytes activation and this excessive neuroinflammatory response could affect the long-term outcome of stroke. The long-term goal of our lab is to understand key components of the CNS that determine neuronal survival and neurorepair, to improve functional outcomes from CNS injury or chronic neurological diseases. One of our research interests is to characterize how microglia cells affect the function of astrocytes and eventually determines the survival of neurons under both physiological and pathological conditions. TGF-β has recently been suggested as a key factor in the maintenance of microglia homeostasis under physiological conditions in adult brain. However, its role regulating injury-induced microglia and astrocyte responses during different stages of pathology development has not been investigated. TGF-β pharmacological modulators (inhibitors and activators) have shown mixed and conflicting results in stroke animal models, depending on the dosage and time of administration. These findings emphasize the importance of precise temporal and cell type specific modulation of this pathway. To precisely investigate the role of TGF-β signaling pathway in microglia maintenance and astrocyte crosstalk, we have developed multiple cell-type specific and temporally inducible ligand or receptor conditional KO mice. Our preliminary data indicates that TGF-β signaling is important in maintaining the resting CNS microglia signature profile under physiological condition and ablation of TGF-β signaling in microglia not only prime microglia cells to pre-inflammatory states, but also activate quiescent astrocytes. Utilizing novel inducible conditional KO mice lines, we will test our central hypotheses that 1)TGF-β signaling is important in the homeostasis of microglia function and its cross-talk with astrocytes under pathophysiological conditions and 2) that modulation of this pathway will lead to altered CNS functional outcome. If successful, the knowledge that will be gained from this proposal is not limited to stroke research but can also have broader impact on the role of TGF-β1 signaling in neuroinflammation regulation and microglia-astrocyte crosstalk in other CNS diseases.


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: 2025 ( Subtotal = $524,821 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/15/2025	NON-COMPETING CONTINUATION	$524,821
														Subtotal = $524,821

Issue Date FY: 2024 ( Subtotal = $509,077 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/8/2024	NON-COMPETING CONTINUATION	$509,077
														Subtotal = $509,077

Issue Date FY: 2023 ( Subtotal = $488,473 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/21/2023	NON-COMPETING CONTINUATION	$488,473
														Subtotal = $488,473

Issue Date FY: 2022 ( Subtotal = $553,741 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/16/2022	NEW	$0
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/10/2022	NEW	$553,741
														Subtotal = $553,741

Grand Total All Awards = $2,076,112

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The role TGF-beta Signaling pathway in microglia and astrocytes homeostasis and cellular interactions

Award Number: R01NS125074

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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