Friday, April 19, 2024 4/19/2024

Imaging retinal leukocyte-endothelial interaction as a diagnostic marker for multiple sclerosis

Award Number: R01NS099431
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY In multiple sclerosis (MS), the most common neurological disease in the working young, inflammatory cells infiltrate the central nervous system (CNS) and attack the myelin-producing cells that are crucial for function and survival of axons. Most patients experience a relapsing-remitting disease course with ever worsening neurological symptoms and, ultimately, disability. Current diagnostic imaging techniques cannot predict relapses because they cannot detect the active leukocyte infiltration into the CNS that leads to clinical disease symptoms downstream. This proposal intends to provide a method that enables non-invasive assessment of this asymptomatic disease activity based on the detection of leukocyte-endothelial interaction (LEI) in the retina by live imaging, which will allow prediction of MS relapses and rapid feedback on treatment response and disease progression. Thus, retinal LEI detection could help transform therapeutic intervention in MS and mitigate the development and severity of disability in MS. LEI, the rolling of white blood cells that is a requirement for leukocyte infiltration, is absent in healthy CNS and considered a hallmark of inflammation. We hypothesize that retinal LEI near the optic nerve head (ONH) indicates active leukocyte infiltration into the CNS that precedes MRI detectable lesions and clinical disease symptoms. The retina is an optically accessible compartment of the CNS that lends itself to optical, intravital imaging through the pupil of the eye. With a scanning laser ophthalmoscope (SLO), custom built for mouse retinal imaging, retinal LEI was detected in early stages of experimental autoimmune encephalomyelitis (EAE), an accepted rodent model of MS, prior to clinical symptoms. Our preliminary data further demonstrated, that pro-inflammatory messengers can reach the retina via transport of cerebrospinal fluid (CSF) and cause retinal LEI, although the retina and optic nerve themselves are not inflamed. In aim 1, we will characterize retinal LEI in EAE and compare its time course to that of leukocyte infiltration into the CNS, as assessed by flow cytometric analysis, and to development of CNS lesions by MRI. Treatment will be administered upon LEI detection and the disease time course compared with untreated controls. In aim 2, we will assess the sensitivity of retinal LEI to remotely detect CNS inflammation. We determine if the location of an inflammatory brain lesion affects the frequency of retinal LEI. Furthermore, MS-relevant cytokines will be injected directly into the CSF to test their ability to elicit retinal LEI. In aim 3, we will develop an adaptive optics (AO) SLO that is specialized for the detection of retinal LEI. Using high-speed scanning and a woofer-tweeter AO architecture, the instrument will generate a field of view that probes the area in and near the optic nerve head, where most LEI would be expected. This cutting-edge instrument will be used in a pilot study to assess retinal LEI in MS patients.


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 = -$1,325 )
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/21/2024	NON-COMPETING CONTINUATION	-$1,325
														Subtotal = -$1,325

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $413,280 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	12/10/2021	NON-COMPETING CONTINUATION	$371,952
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	3/28/2022	NON-COMPETING CONTINUATION	$41,328
2022	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $413,280

Issue Date FY: 2021 ( Subtotal = $413,280 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/23/2021	NON-COMPETING CONTINUATION	$413,280
														Subtotal = $413,280

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $411,937 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/9/2019	NON-COMPETING CONTINUATION	$411,937
														Subtotal = $411,937

Issue Date FY: 2018 ( Subtotal = $409,818 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/17/2018	NON-COMPETING CONTINUATION	$409,818
														Subtotal = $409,818

Issue Date FY: 2017 ( Subtotal = $416,872 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/11/2017	NEW	$416,872
														Subtotal = $416,872

Grand Total All Awards = $2,063,862

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Imaging retinal leukocyte-endothelial interaction as a diagnostic marker for multiple sclerosis

Award Number: R01NS099431

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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