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The molecular basis for the translocation of fungi from blood-to-brain.

Award Number: R01NS110800
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: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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The molecular basis for the translocation of fungi from blood-to-brain. - PROJECT ABSTRACT Infections of the central nervous system (CNS) caused by fungi have the highest morbidity and mortality when compared to other causative agents of CNS infections. Cryptococcus neoformans (Cn), Candida albicans, Aspergillus spp., Mucor, Coccidioides spp., and Histoplasma capsulatum are the most common cause of fungal brain infections resulting in a chronic instead of an acute or subacute meningoencephalitis. The long-term goal will investigate the spatio-temporal organization and molecular basis of Cn trafficking across the BBB and investigate a cross-talk between a transcellular mechanism and the opening of a paracellular path in response to Cn infection. Given our preliminary data and published studies, we propose that Cn represents an excellent model pathogen with which to determine the mechanisms that pathogenic fungi use to breach the BBB and enter the CNS. In our efforts to understand the molecular basis mediating the Cn-brain endothelium interactions, we identified a tyrosine kinase receptor (EphA2-TKR) as the central player. The central hypothesis states that fungal cells penetrate the BBB by engaging EphA2-TKR in order to access a binary path into the CNS. To test our hypothesis, we will investigate the interplay between fungal cells, EphA2-TRK and its downstream signaling components in mediating the translocation of Cn from blood-to-brain. The following specific aims will test the hypothesis: SA1 will investigate a Cn-induced CD44-mediated transactivation of EphA2-TKR activity and the interactome of EphA2-TKR. SA2 will examine the role of EphA2-TKR in upregulating vesicular traffic of Cn and resolve whether Cn-induced activity of EphA2-TKR promotes a co-regulation of a transcellular and paracellular pathway. SA3 will resolve the contribution of EphA2-TKR activity to the translocation of Cn from blood-to-brain in vivo and examine the molecular basis of changes in the permeability of the BBB when challenged by Cn. The proposed research is innovative because it will for the first time, detail the key players that promote the internalization and trafficking of fungi across the BBB. The innovation extends to our published studies that identified EphA2-TKR in the brain endothelium as a central element in mediating the migration Cn from blood-to-brain. This along with the notion that crossing of the BBB is initiated by a fungal-induced CD44-transactivation of EphA2-TKR to trigger a pathological use of endocytosis (and possibly a secondary paracellular path) in brain endothelial cells is a paradigm shift from our current understanding. We have proposed experiments that will use multiple complementary approaches to tease apart the molecular interaction between Cn, EphA2- TKR and CD44 while also using proximity-dependent labeling to identify the interactome of EphA2-TKR. The knowledge gained from our studies will make a significant contribution to fungal pathogenesis of the CNS, because it remains significantly understudied, and this work will spearhead the development of molecules that could block fungal entry and thus serve as pre- emptive or prophylactic therapy in patients at risk for developing fungal meningoencephalitis.


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: 2024 ( Subtotal = $400,669 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/26/2024	SUPPLEMENT FOR EXPANSION	$50,304
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	4/11/2024	NON-COMPETING CONTINUATION	$25,284
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/25/2024	NON-COMPETING CONTINUATION	$325,081
														Subtotal = $400,669

Issue Date FY: 2023 ( Subtotal = $816,824 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	2/8/2023	SUPPLEMENT FOR EXPANSION	$24,765
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	5/3/2023	SUPPLEMENT FOR EXPANSION	$374,221
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/30/2023	NON-COMPETING CONTINUATION	$361,201
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/31/2023	SUPPLEMENT FOR EXPANSION	$56,637
														Subtotal = $816,824

Issue Date FY: 2022 ( Subtotal = $392,526 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/22/2022	NON-COMPETING CONTINUATION	$36,121
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/7/2022	SUPPLEMENT FOR EXPANSION	$31,325
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/19/2022	NON-COMPETING CONTINUATION	$325,080
														Subtotal = $392,526

Issue Date FY: 2021 ( Subtotal = $361,201 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/15/2021	NON-COMPETING CONTINUATION	$361,201
														Subtotal = $361,201

Issue Date FY: 2020 ( Subtotal = $348,877 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/2/2020	NEW	$348,877
														Subtotal = $348,877

Grand Total All Awards = $2,320,097

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The molecular basis for the translocation of fungi from blood-to-brain.

Award Number: R01NS110800

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: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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