# Metabolic Modulation of SK/IK Channels for Cerebrovascular Endothelial Protection Related to Alzheimer's Disease

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2020 · $399,345

## Abstract

Growing evidence supports the concept that Alzheimer’s disease (AD) is fundamentally a metabolic/cerebro-
microvascular disease with molecular/biochemical features that correspond with diabetes mellitus (DM).
Cerebrovascular endothelial dysfunction is emerging as a major risk factor for AD. Importantly, SK/IK channels
have been reported to play a key role for neurodegeneration and cerebrovascular regulation. However,
mechanisms and the therapeutic strategies for endothelial SK/IK channels to mitigate metabolic and
cerebrovascular disturbances in AD are lacking. Thus, the overall goal of this supplement project is focused on
the mechanism and treatment of endothelial SK/IK channel modulation on AD-induced neurovascular
dysfunction. We observed that amyloid-(A) peptide (A) causes endothelial SK/IK dysfunction. Thus, we
hypothesized that AD may cause metabolic dysregulation of SK/IK channel function, leading to cerebrovascular
endothelial dysfunction and neurovascular injury; and metabolic modulation and/or SK/IK activation will enhance
cerebrovascular SK/IK activity leading to normalized neurovascular endothelial function/relaxation. Importantly,
this is the same basic hypothesis as in the parent R01 grant focused on metabolic modulation in coronary
endothelium and microvasculature. We will use the same approaches, specialized reagents, and similar
experimental strategies as detailed in my current RO1 to complete the Aims of this supplement proposal. Thus,
we will test our hypothesis by completing 2 specific aims: Ami 1) to evaluate if metabolic modulation and/or
SK/IK activation can alleviate A-induced changes in SK/IK channel activity in the in-vitro. Brain
microvascular endothelial cells with or without DM will be treated with soluble A in the presence/absence of
PKC, Nox, mROS inhibitors, NADH/NAD, SK/IK small molecule activators, adenoviral overexpression/mutation
of endothelial SK/IK, respectively. Endothelial SK/IK channel recording (patch clamp method) and metabolic
alterations will be assessed. Aim 2) to Determine AD-induced changes in cerebra-microvascular reactivity,
SK/IK activation-induced endothelium-dependent cerebral arteriolar relaxation and if metabolic
modulation and/or SK/IK-activator can improve cerebra-microvascular reactivity and cognitive function
in the STZ-induced AD mice and STZ-treated SK/IK KO mice. We will treat STZ-induced AD mice and STZ
treated SK/IK knockout (KO) mice with/without Nox, mROS, PKC inhibitors, SK/IK activators, respectively for 4
weeks followed by Morris Water Maze testing for cognitive function and assessment of neurovascular
morphologic/metabolic changes. We will harvest cerebral arterioles from WT mice and STZ-induced-AD mice
and STZ-treated SK/IK KO mice for analyzing cerebral arteriolar reactivity and SK/IK activity. This project will
improve our understanding of AD-related cerebrovascular dysfunction by studying novel mechanisms
responsible for metabolic dysregulation of endothelial SK chan...

## Key facts

- **NIH application ID:** 10123056
- **Project number:** 3R01HL136347-04S1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Jun Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,345
- **Award type:** 3
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123056

## Citation

> US National Institutes of Health, RePORTER application 10123056, Metabolic Modulation of SK/IK Channels for Cerebrovascular Endothelial Protection Related to Alzheimer's Disease (3R01HL136347-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10123056. Licensed CC0.

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