# A new model system to study brain aging and neurodegeneration

> **NIH NIH R21** · BROWN UNIVERSITY · 2020 · $436,854

## Abstract

PROJECT SUMMARY
This proposal is motivated by the scarcity of studies and approaches that directly investigate the mechanisms
underlying aging and neurodegeneration in the context of physiologically aged neurons. This gap in our
knowledge is significant because neurodegeneration is an age-related condition. This long-term goal of this work
is to understand the mechanisms responsible for degeneration of the hypothalamus, a key region involved in
neuroendocrine regulation. The objective of this proposal is to use cellular reprogramming methods to establish
a new platform to investigate the mechanisms of degeneration of a particular hypothalamic neuronal subtype:
POMC neurons. POMC neurons are a rare cell type in the brain with a critical neuroendocrine function. The
hypothesis is that directly reprogrammed iPOMCs from aged animals and models of Alzheimer's disease will
provide a useful system to uncover the mechanisms of POMC aging and degeneration. This hypothesis is
supported by strong preliminary data and will be tested through two specific aims: 1) Establish and optimize an
in vitro system to study how POMC neurons age and 2) Generate iPOMC cells with mutations associated with
familial AD. The first aim will characterize the age-associated phenotypes in iPOMC cells in the context of
physiological aging. The second aim will, for the first time, establish a system to study a particular hypothalamic
cell type in the context of Alzheimer's Disease. This system is a highly innovative approach to studying rare but
critical cell types in the context of aging and neurodegeneration. Moreover, it can be expanded in future studies
to generate other hypothalamic cell types, perform mechanistic studies, and implement small molecule screens
to study and treat neuroendocrine dysfunction. This work is significant because it will provide a system to study
the mechanisms responsible for aging of particular hypothalamic neuronal subtypes, which currently is not
feasible with available tools. Ultimately, this approach has the potential to transform our understanding of
neurodegenerative disease and lead to new therapies to prevent and treat these conditions.

## Key facts

- **NIH application ID:** 10109804
- **Project number:** 1R21AG070527-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Ashley E Webb
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,854
- **Award type:** 1
- **Project period:** 2020-09-11 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109804

## Citation

> US National Institutes of Health, RePORTER application 10109804, A new model system to study brain aging and neurodegeneration (1R21AG070527-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10109804. Licensed CC0.

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