A systems biology approach to understand the role of klotho and estrogen in combating neurodegeneration

The National Institute on Aging awarded CAL Poly Humboldt Sponsored Programs Foundation $267,525 on September 5, 2026, under the Aging Research program (CFDA 93.866) to conduct systems biology research investigating the role of klotho and estrogen in combating neurodegeneration associated with Alzheimer's disease.

The project applies ordinary differential equations and agent-based modeling to simulate molecular signaling cascades, cellular metabolic reprogramming, and spatial microenvironment dynamics in the hippocampus. Three specific aims guide the research: extending an ODE model of NF-κB signaling to incorporate estrogen and klotho and elucidate their regulatory roles in inflammation; developing a multiscale ODE model to explore how apolipoprotein E4 (APOE4) and estrogen co-regulate microglial dysfunction and blood-brain barrier breakdown; and integrating these insights into a spatially explicit agent-based model of the hippocampus to capture how estrogen and klotho modulate immune-cell behavior and barrier permeability over time. The work addresses sex-specific vulnerability to Alzheimer's disease, particularly in the presence of the APOE4 genotype, by investigating the interplay between hormonal decline, immune dysregulation, and metabolic dysfunction.

Work is performed in Arcata, California. The period of performance runs from September 5, 2026 to August 31, 2029. The assistance type is a Project Grant.

Abstract

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.