# Hypothalamic astrocyte-neuron relationship links overnutrition to hypertension

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $628,012

## Abstract

ABSTRACT/SUMMARY
Obesity-related hypertension (OHT), an etiologically prevalent disorder accounting for ~75% of patients with
hypertension, is however hard to control, and this clinical difficulty is related to the specific yet much unclear
mechanism of OHT. Having recently appreciated that the hypothalamic neuronal basis of OHT is significantly
due to obesity-induced IKKβ/NF-κB-dependent hypothalamic inflammation, the long-term objective of this
research is to study hypothalamic neural types and molecular cascades that mediate OHT. In preliminary
studies, using mouse models with hypothalamic astrocytic IKKβ/NF-κB activation or inhibition, supportive
evidence has been obtained suggesting that hypothalamic astrocytes have site-specific multiple programs in
causing hypertension. Hence, the hypothesis of this proposal is, under chronic high-fat diet feeding,
hypothalamic astrocytic IKKβ/NF-κB is activated to cause OHT, mechanistically mediated by (a) converging
effects of adipokines and consequent hypothalamic ER stress due to blood-brain barrier (BBB) breakdown, (b)
activation of POMC neurons due to astrocytic cytokine-induced dysfunction of arcuate DA neurons, and (c)
excess of α-MSH and glutamate in the PVN due to impaired astrocytic clearance. Three Aims are proposed to:
(1) study the neuroanatomic and BBB breakdown basis for the role of astrocytic IKKβ/NF-κB in OHT; (2) study
altered MBH astrocyte-neuron relationship in obesity and the contribution to OHT; and (3) study altered PVN
astrocyte-neuron relationship in obesity and the contribution to OHT. Experiments will be carried out using
mouse models of site- and cell-specific IKKβ/NF-κB manipulations as well as manipulations of the downstream
molecular pathways in astrocytes and relevant neurons. Blood pressure phenotypes will be examined in these
models in the context of dietary obesity or genetic manipulations of proposed mechanisms. Astrocytic changes,
downstream programs, and further downstream neuronal alterations will be rigorously analyzed. Overall,
successful completion of this project can yield new insights into the hypothalamic mechanism of OHT and
enlighten the strategy of targeting hypothalamic astrocytic programs in combating this disease.

## Key facts

- **NIH application ID:** 9896742
- **Project number:** 5R01HL147477-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Dongsheng Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $628,012
- **Award type:** 5
- **Project period:** 2019-03-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896742

## Citation

> US National Institutes of Health, RePORTER application 9896742, Hypothalamic astrocyte-neuron relationship links overnutrition to hypertension (5R01HL147477-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896742. Licensed CC0.

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