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Molecular Mechanisms of the Blood Brain Barrier Function and Regulation

Award Number: R35NS116820
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: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Molecular Mechanisms of the Blood Brain Barrier Function and Regulation - Project Summary/Abstract: The central nervous system (CNS) requires a tightly controlled environment free of various toxins and pathogens to provide the proper chemical composition for synaptic transmission. This environment is maintained by the `blood brain barrier' (BBB), which is composed of highly specialized blood vessels whose endothelial cells display specialized tight junctions and unusually low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux. While BBB breakdown has recently been associated to initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hampered our ability to manipulate the BBB in disease. Our recent discoveries changed our understanding of what makes the BBB impermeable. The BBB is formed by a single layer of endothelial cells that lines the walls of the brain's blood vessels. Historically, the restrictive feature of BBB has been attributed to the specialized tight junctions between adjacent endothelial cells. However, substances can also cross the endothelial layer by transcytosis, when material enters endocytic vesicles that are trafficked across the cell. We discovered that transcytosis is actively inhibited in brain endothelial cells to ensure BBB integrity. Our findings suggest that molecular pathways inhibiting transcytosis could be targeted to open the BBB for CNS therapeutics.We have also identified over 200 BBB candidate genes that are enriched in CNS endothelial cells compared to periphery endothelial cells. I propose to launch major new efforts leading to a major expansion in the scope of our work in the field of BBB. I will take the next eight years to bring my lab to the next level to (1) identify the full list of key BBB regulators in CNS endothelial cells, (2) understand what signals from non-endothelial cells maintain and regulate BBB permeability, and (3) determine how BBB permeability dynamically changes during different physiological and pathological conditions. We will also begin to work on translating findings from these studies to therapies. We will use a combination of mouse genetics, imaging, molecular, cell biology, and biochemical approaches. The experiments described here represent a major expansion in the scope of our work. Achieving the goals outlined here could have a major impact on neurology, enabling clinicians to open the BBB for transient delivery of drugs to the CNS, and conversely to close the BBB to slow the progression of neurodegenerative diseases. Given the transcriptome screens we have recently performed, the model systems we have devised, and the imaging tools we have recently developed, my lab is in a unique position to reveal the molecular and cellular mechanisms of the BBB.


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: 2026 ( Subtotal = $1,009,297 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/17/2026	NON-COMPETING CONTINUATION	$1,009,297
														Subtotal = $1,009,297

Issue Date FY: 2025 ( Subtotal = $1,009,297 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/21/2025	NON-COMPETING CONTINUATION	$1,009,297
														Subtotal = $1,009,297

Issue Date FY: 2024 ( Subtotal = $979,016 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/29/2024	NON-COMPETING CONTINUATION	$979,016
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $979,016

Issue Date FY: 2023 ( Subtotal = $1,009,297 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/13/2023	NON-COMPETING CONTINUATION	$1,009,297
2023	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,009,297

Issue Date FY: 2022 ( Subtotal = $1,009,297 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/20/2022	NON-COMPETING CONTINUATION	$1,009,297
2022	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,009,297

Issue Date FY: 2021 ( Subtotal = $1,009,297 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/9/2021	NON-COMPETING CONTINUATION	$1,009,297
														Subtotal = $1,009,297

Issue Date FY: 2020 ( Subtotal = $1,009,297 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/24/2020	NEW	$1,009,297
														Subtotal = $1,009,297

Grand Total All Awards = $7,034,798

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Molecular Mechanisms of the Blood Brain Barrier Function and Regulation

Award Number: R35NS116820

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: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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