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Neuroinflammation and microglial Kv1.3 in Parkinsons disease

Award Number: R01NS100090
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Neuroinflammation and microglial Kv1.3 in Parkinsons disease - A sustained neuroinflammatory insult characterized by massive microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson’s disease (PD). Interestingly, microglia constitute a particularly attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding dopaminergic degeneration. Recent studies pertaining to neuroinflammation in PD have generated tremendous enthusiasm because α-synuclein (αSn) aggregates can serve as an endogenous antigen triggering neurotoxicity by provoking a potent microglia-mediated proinflammatory response. Also, accumulating evidence reveals that misfolded αSyn spreads through a cell-to-cell transmission mechanism, contributing to the propagation of α yn pathology to neighboring neuronal and glial cells, possibly augmenting the progression of PD. Despite these advances, the fundamental neurobiological mechanisms regulating sustained microglia activation and neuroinflammatory cascades during pathogenic αSyn aggregate stimulation remain to be established. Thus, identification of key targets contributing to sustained microglia activation could provide potential targets to slow the progression of the disease. We recently obtained exciting new data showing that the voltage-gated potassium channel Kv1.3 is highly upregulated in aggregated αSyn-stimulated primary microglia and animal models of PD, as well as in human PD postmortem samples. Importantly, patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. Additional preliminary results suggest that a proinflammatory kinase PKCδ plays a role in αSyn aggregate-induced Kv1.3 upregulation. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) characterize Kv1.3 upregulation and activation of pro-inflammatory microglia in animal models of αSyn aggregate-induced neurotoxicity, and define the role of Kv1.3 in microglia-mediated neuroinflammation and augmentation of the neurodegenerative process in nigrostriatal dopaminergic neurons in PD, (ii) unravel the molecular underpinning of Kv1.3 channel upregulation in microglia during an αSyn aggregate-induced neuroinflammatory insult, and (iii) establish the role of Kv1.3 in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn protein aggregation in animal models of PD. We will use multiple model systems and state-of-the-art biochemical, cellular, neurophysiological, histological and neurochemical approaches to achieve these specific aims. Overall, we anticipate that our proposed studies will provide novel mechanistic insights into sustained microglia activation and its role in neuroinflammatory processes in PD disease progression and will offer novel therapeutic targets to curtail neuroinflammatory responses in PD and other related neurodegenerative disorders.


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: 2023 ( Subtotal = -$6,867 )
2023	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,867
														Subtotal = -$6,867

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	5/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$71,244
2022	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,549
2022	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/17/2021	NON-COMPETING CONTINUATION	-$373,549
2022	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	5/31/2022	NON-COMPETING CONTINUATION	-$71,244
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $373,549 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/16/2021	NON-COMPETING CONTINUATION	$373,549
														Subtotal = $373,549

Issue Date FY: 2020 ( Subtotal = $374,268 )
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/27/2020	NON-COMPETING CONTINUATION	$374,268
														Subtotal = $374,268

Issue Date FY: 2019 ( Subtotal = $374,658 )
2019	2019	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/25/2019	NON-COMPETING CONTINUATION	$374,658
														Subtotal = $374,658

Issue Date FY: 2018 ( Subtotal = $374,658 )
2018	2018	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/2/2018	NON-COMPETING CONTINUATION	$37,466
2018	2018	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/2/2018	NON-COMPETING CONTINUATION	$337,192
														Subtotal = $374,658

Issue Date FY: 2017 ( Subtotal = $385,584 )
2017	2017	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/31/2017	NEW	$385,584
														Subtotal = $385,584

Grand Total All Awards = $1,875,850

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Neuroinflammation and microglial Kv1.3 in Parkinsons disease

Award Number: R01NS100090

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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