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NIH grant 1R15AG101767-01: A Systems Biology Approach to Understand the Role of Klotho and Estrogen in Combating Neurodegeneration
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Kamila Larripa. Award: $267525.
Start: 2026-09-05T00:00:00.
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.document fetched 2026-09-13 02:45