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Metabolic and Hormonal Mechanisms of VCID

Award Number: R01NS110749
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: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Metabolic and Hormonal Mechanisms of VCID - PROJECT SUMMARY/ABSTRACT There are currently no effective therapies to reduce vascular contributions to cognitive impairment and dementia (VCID). The objective of the parent R01 was to build an understanding of the important interaction between menopause and metabolic health on VCID and identify a novel therapeutic approach to treat VCID in post- menopausal females. We demonstrated that menopause causes weight gain, glucose intolerance, and exacerbates cognitive symptoms in VCID. Conversely, using a 17β-estradiol prodrug therapy we were able to restore cognitive function after menopause. Further, we have preliminary data to suggest reduced endothelial cell (EC) function in menopause may be a contributing factor to cognitive impairment and that estrogen receptor signaling has protective effects on brain ECs (in vivo in mice and in vitro in human ECs). Given that over 80% of individuals with Alzheimer’s disease (AD) have underlying VCID pathology that contributes to dementia progression, the objectives of the current proposal are to define the therapeutic potential of increasing estrogen signaling in the brain in several dementia models and to identify common underlying cellular mechanisms. Despite the high clinical prevalence of multiple etiology dementia (MED), very few studies have examined how AD and VCID interact to produce MED. Our preliminary data show early hippocampal gene changes in AD that are associated with reduced blood brain barrier function. We also discovered that the brain EC translatome is altered in both AD and MED models, even prior to the development of cognitive symptoms, suggesting that targeting brain ECs may be an effective preventative strategy for MED. DHED is a brain-specific 17β-estradiol prodrug that is inactive in the periphery but gets converted to 17β-estradiol only in the brain and is able to activate all 3 estrogen receptors. Given that we, and others, have demonstrated numerous protective effects of estradiol on the cerebral vasculature and we have demonstrated that DHED improves memory after menopause in a dose-dependent manner, we hypothesize that DHED can be used as a preventative strategy to mitigate the vascular impact of (peri-)menopause on MED via improving endothelial health. Since pathology is diverse in MED, we utilize two MED models with different pathologies. Aim 1 will test the hypothesis that peri-menopause induces EC translatome changes and exacerbation of MED pathology that is distinct from changes during menopause. Aim 2 will test the hypothesis that DHED therapy during peri-menopause can reduce underlying pathology and delay onset of cognitive symptoms in MED. Aim 3 will test the hypothesis that DHED improves EC function in human iPSC-derived ECs, with greater protection in cells from APOE4/4 donors. We anticipate these studies will provide mechanistic insight that will facilitate future interventions to decrease the burden of dementia by defining the therapeutic potential of DHED in MED and identify mechanisms by which DHED provides protection in the presences of multiple vascular risk factors.


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 = $0 )
2025	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/19/2025	COMPETING CONTINUATION	$27,276
2025	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/19/2025	NON-COMPETING CONTINUATION	-$27,276
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $828,967 )
2024	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	9/17/2024	COMPETING CONTINUATION	$828,967
2024	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $828,967

Issue Date FY: 2023 ( Subtotal = $355,088 )
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/5/2023	NON-COMPETING CONTINUATION	$355,088
														Subtotal = $355,088

Issue Date FY: 2022 ( Subtotal = $355,088 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/29/2022	NON-COMPETING CONTINUATION	$355,088
														Subtotal = $355,088

Issue Date FY: 2021 ( Subtotal = $355,088 )
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/17/2021	NON-COMPETING CONTINUATION	$355,088
														Subtotal = $355,088

Issue Date FY: 2020 ( Subtotal = $360,951 )
2020	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/5/2020	NON-COMPETING CONTINUATION	$360,951
														Subtotal = $360,951

Issue Date FY: 2019 ( Subtotal = $376,350 )
2019	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/9/2019	NEW	$376,350
														Subtotal = $376,350

Grand Total All Awards = $2,631,532

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Metabolic and Hormonal Mechanisms of VCID

Award Number: R01NS110749

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: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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