Friday, October 31, 2025 10/31/2025

Development of ER-beta Agonists to Treat Post-Menopausal Memory Decline

Award Number: R15GM118304
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2022

Group Awards By:

View Award Description

Development of ER-beta Agonists to Treat Post-Menopausal Memory Decline - Project Summary/Abstract Estrogen level decreases in post-menopausal women have been shown to increase the risk of memory loss and Alzheimer’s disease. While these effects might be mitigated using hormone replacement therapy, traditional estrogen-based hormone therapies also lead to increased risk of cancer, heart disease and stroke. These adverse effects are mediated predominantly by estrogen receptor-alpha (ER). Relevant to menopause, aging significantly reduces levels of ERand ERin the hippocampus, suggesting an association with age-related memory decline; but, ERremains the predominant isoform. We hypothesize that an optimal treatment for age-related memory decline in post-menopausal women may be via treatment that selectively activates hippocampal ER. Our long-term goal is to develop safer and more selective ER agonists as therapeutics for treating dementia in post-menopausal women. Our objective is to optimize and characterize a novel class of molecules comprised of a 4-hydroxymethyl- cyclohexane ring tethered to a phenol ring, making it an A-C estrogen that closely resembles the naturally occurring estrogen molecule, but lacking the B and D rings. The rationale for the proposed research is that it will provide essential foundational knowledge about estrogenic regulation of cognition that will advance the development of novel treatments; and, it will provide mechanistic insights into the remarkable ER selectivity that can be achieved with simplified versions of the estrogen itself. Our Aims Are to:  Aim 1. Characterize and optimize the structural features of ISP358-2 that are responsible for its high ER selectivity. We will use docking to guide design and optimization of ISP358-2 based on activity in cell-based (ER vs. ER agonist activity) assays, and then demonstrate in vivo efficacy for memory consolidation.  Aim 2. Determine mechanism of ISP538-2 ER agonist selectivity. We will measure and characterize ability of optimized ISP358-2 and control (PPT, E2) compounds to cause agonist conformational changes needed to recruit brain-relevant coactivator, thereby inducing transcription.  Aim 3. Establish the therapeutic potential of the optimized ISP358-2 lead molecule by determining the neural mechanism through which it enhances memory consolidation. We will use intracranial infusions to measure the extent to which ISP358-2 acts like an ER agonist to trigger rapid cell signaling, alter hippocampal morphology, and enhance memory.


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: 2023 ( Subtotal = -$19,750 )
2023	2018	CONCORDIA UNIVERSITY, INC.	12800 N LAKE SHORE DR	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	000	2	6/5/2023	COMPETING CONTINUATION	-$19,750
														Subtotal = -$19,750

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	CONCORDIA UNIVERSITY WISCONSIN, INC.	12800 N LAKESHORE DR	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	000	2	10/23/2018	COMPETING CONTINUATION	$0
2019	2018	CONCORDIA UNIVERSITY WISCONSIN, INC.	12800 N LAKESHORE DR	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	002	2	2/3/2019	COMPETING CONTINUATION	$2,016
2019	2015	CONCORDIA UNIVERSITY WISCONSIN, INC.	12800 N LAKESHORE DR	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	001	1	2/3/2019	NEW	-$2,016
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $479,363 )
2018	2018	CONCORDIA UNIVERSITY WISCONSIN, INC.	12800 N LAKESHORE DR	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	000	2	9/18/2018	COMPETING CONTINUATION	$479,363
														Subtotal = $479,363

Issue Date FY: 2015 ( Subtotal = $340,674 )
2015	2015	CONCORDIA UNIVERSITY WISCONSIN	12800 N LAKE SHORE DRIVE 9 W	MEQUON	WI	53097	OZAUKEE	USA	Biomedical Research and Research Training	000	1	8/24/2015	NEW	$340,674
														Subtotal = $340,674

Grand Total All Awards = $800,287

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Development of ER-beta Agonists to Treat Post-Menopausal Memory Decline

Award Number: R15GM118304

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer