Thursday, September 18, 2025 9/18/2025

Molecular tools to decipher communication across the blood-brain barrier

Award Number: DP5OD033381
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Molecular tools to decipher communication across the blood-brain barrier - Project Summary/Abstract The blood-brain barrier (BBB) maintains brain health by protecting the brain from the bloodstream. These barrier properties frustrate the treatment of nearly all brain disorders, representing one of the largest challenges in neuroscience and drug delivery. Yet, intriguingly, recent studies have discovered a variety of surprising peripheral influences on brain function, hinting at the existence of underappreciated modes of communication across the BBB. Indeed, while canonical BBB properties, such as paracellular tight junctions and minimal caveolin-mediated transcytosis, have been established via a handful of standard tracers, it remains unclear whether these tracers fully represent the BBB’s physiological interactions with and permeability to the thousands of circulating proteins and cells it is constantly exposed to. By developing methods to tag and track the blood plasma proteome, I recently observed an unexpected degree and diversity of protein transport into the healthy adult brain. Thus, I hypothesize that brain health is maintained not just by BBB impermeability—but by specific routes of blood-to-brain communication actively facilitated by the BBB. Specifically, I propose that there are three logical routes for how peripheral information is communicated across the healthy BBB: the direct transport of proteins into the brain; the responsive relay of proteins made by the BBB into the brain; and the BBB-licensed migration of peripheral immune cells into the brain. By combining proteome tagging techniques with bioorthogonal chemistries, each proposed aim explores one independent route to systematically reveal the identities and mechanisms of the signals transmitted via the healthy BBB. I will begin by creating a first catalog of plasma proteins that directly cross the BBB and quantifying their permeabilities (Aim 1). I will subsequently characterize a new BBB relay function by deducing the signals the BBB secretes into the brain in response to peripheral cues (Aim 2). Lastly, I will elucidate neuroimmune surveillance by determining the BBB sites and molecules enabling healthy immune cell migration into the brain (Aim 3). Together, these studies will expand our understanding of how the BBB maintains brain health and enable new studies exploring the neurological functions of BBB-permeable proteins and cells in health, aging, and disease. Our results will also provide a comprehensive set of functional targets to enhance drug delivery to the brain, reveal new mechanisms to understand and blunt neuroinflammation, and generate innovative tools to decipher intercellular communication for broad use across disciplines.


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 = $1,013,752 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Trans-NIH Research Support	001	5	8/15/2025	EXTENSION WITH OR WITHOUT FUNDS	$945,000
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Trans-NIH Research Support	002	4	8/15/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Trans-NIH Research Support	000	4	7/8/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$472,500
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Trans-NIH Research Support	003	3	9/4/2025	NON-COMPETING CONTINUATION	-$403,748
														Subtotal = $1,013,752

Issue Date FY: 2024 ( Subtotal = $403,750 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Trans-NIH Research Support	000	3	8/2/2024	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2023 ( Subtotal = $403,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Research Support	000	2	9/1/2023	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $385,300 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Research Support	000	1	9/14/2022	NEW	$385,300
														Subtotal = $385,300

Grand Total All Awards = $2,206,552

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Molecular tools to decipher communication across the blood-brain barrier

Award Number: DP5OD033381

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/14/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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