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A Systems Biology Approach to Understand the Role of Klotho and Estrogen in Combating Neurodegeneration

Award Number: R15AG101767
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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A Systems Biology Approach to Understand the Role of Klotho and Estrogen in Combating Neurodegeneration - Project Summary Title: A Systems Biology Approach to Understand the Role of Klotho and Estrogen in Combating Neurodegen- eration Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by immune dysregulation, metabolic dysfunction, and progressive neuronal loss. Despite decades of research focused on amyloid-beta pathology, limited therapeutic success has prompted a shift toward understanding alternative mechanisms that drive disease progression. Women are disproportionately affected by AD, particularly in the presence of the APOE4 genotype, and evidence increasingly implicates hormonal decline and immune-metabolic dysfunction in this sex-specific vulnerability. This proposal adopts a systems biology framework to investigate the interplay between estrogen signaling, Klotho expression, and APOE genotype in regulating microglial activity, metabolism, and blood-brain barrier (BBB) integrity. The central hypothesis is that hormonal and genetic modulation of immune and metabolic path- ways creates a window of vulnerability to neurodegeneration that can be predicted and modulates. Using both ordinary differential equations (ODE) and agent-based models (ABM), this project will simulate molecular signaling cascades, cellular metabolic reprogramming, and spatial microenvironment dynamics in the hippocam- pus. Three Specific Aims will guide this research: 1. Extend an ODE model of NF-κB signaling to incorporate estrogen and Klotho, elucidating their regulatory roles in inflammation. 2. Develop a multiscale ODE model to explore how APOE4 and estrogen co-regulate microglial dysfunction and BBB breakdown. 3. Integrate these insights into a spatially explicit agent-based model of the hippocampus, capturing how estrogen and Klotho modulate immune-cell behavior and barrier permeability over time. In addition to advancing understanding of sex- and genotype-specific AD mechanisms, this project will train undergraduate students in interdisciplinary modeling, coding, and biomedical research. Students will participate in all phases of the project, including model construction, data integration, simulation, and dissemination of findings at conferences and in peer-reviewed publications. The proposed work has the potential to uncover novel therapeutic targets and timing strategies, while simultane- ously supporting the research infrastructure and educational mission of a primarily undergraduate institution.


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 = $267,525 )
2026	2026	CAL POLY HUMBOLDT SPONSORED PROGRAMS FOUNDATION	1 HARPST ST	ARCATA	CA	95521	HUMBOLDT	USA	Aging Research	000	1	9/3/2026	NEW	$267,525
														Subtotal = $267,525

Grand Total All Awards = $267,525

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A Systems Biology Approach to Understand the Role of Klotho and Estrogen in Combating Neurodegeneration

Award Number: R15AG101767

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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