NIH grant: Targeting novel molecular pathways to improve neurological outcomes after chronic hypoperfusion-induced ischemic brain injury (1I01RD001196-01A1)

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NIH grant 1I01RD001196-01A1: Targeting novel molecular pathways to improve neurological outcomes after chronic hypoperfusion-induced ischemic brain injury
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Jun  Chen. Award: $.
Start: 2026-10-01T00:00:00.
Significance to VA: Vascular cognitive impairment and dementia (VCID) is a common disorder in elderly
veterans. Molecular mechanisms underlying clinical symptoms of VCID are closely related to chronic cerebral
hypoperfusion (CCH)-induced ischemic brain injury. Thus, successful therapies for VCID hinge on elucidating
cellular and molecular processes underlying ischemic damage, microvessel destruction, and cognitive decline.
Innovation and Impact: A fundamental mechanism underlying irreparable vascular injuries is a persistent
proinflammatory milieu. Endothelial cells (ECs), microglia (Mi), and macrophages (MΦ) are key mediators of
inflammatory responses in ischemic brain injury. EC inflammation leads to circulatory impairments and disruption
of the blood-brain barrier (BBB). Phenotypic shifts in Mi/MΦ orchestrate interactions with ECs in the
neurovascular unit and regulate blood flow. Thus, careful titration of inflammatory responses in ECs and Mi/MΦ
may improve blood circulation and alleviate VCID. Our main objective is to improve the integrity of the
neurovascular unit under CCH, as a potential strategy to slow cognitive decline in veterans disabled by VCID.
Salt-inducible kinases such as SIK1/3 control gene expression by acting directly on specific transcription factors
and shift immune balance toward pro-inflammatory phenotypes. To date, however, it is not known if SIKs regulate
EC/vascular integrity and Mi/MΦ phenotypes in the context of VCID. Irrespective of the direction of the outcomes,
the Aims will shed new light on the understudied role of cell-specific SIKs in a clinically relevant VCID model.
Positive outcomes will help guide clinical trials to evaluate SIK-based therapies in chronic cerebral hypoxia and
may support translation of SIK inhibitors to temper inflammation in multiple forms of dementia.
Specific Aims: Our pilot studies support a novel role for SIK1/3, as a master switch toward inflammatory EC
and Mi/MΦ phenotypes in VCID: 1) Single-cell RNA-seq data predict that SIK1 and SIK3 are mainly expressed
in ECs and Mi/MΦ and are further elevated 14d after bilateral common carotid artery stenosis (BCAS)-induced
VCID. 2) SIK1 and SIK3, but not SIK2, contribute to cognitive dysfunction after BCAS. 3) Cell-specific SIK1 and
SIK3 double-knockout in Mi/MΦ (SIK1/3 mKO) or ECs (SIK1/3 eKO) alleviate cognitive deficits in BCAS-induced
VCID mice. 4) A selective pan-SIK inhibitor confers remarkable, sustained brain protection in VCID mice,
resolving inflammation and improving cerebral blood flow, BBB integrity, neuronal survival, and cognitive
functions for at least 5 weeks. Based on pilot data, we hypothesize that inhibition of SIK expression or function
mitigates hippocampal neurodegeneration and cognitive decline by reducing EC inflammation and microvascular
dysfunction, and by boosting inflammation-resolving Mi/MΦ responses in VCID mice.
Aim 1: Test the therapeutic potential of a selective SIK inhibitor against long-term BCAS deficits in aged mice.
Aim 2: Test if SIK1/3 expression in ECs promotes brain inflammation, impeding EC function, BBB integrity,
cerebral blood flow, hippocampal and white matter integrity, and cognitive functions after BCAS.
Aim 3: Test if SIK1/3 expression in Mi/MΦ induces inflammatory, neurotoxic Mi/MΦ responses that worsen
vascular dysfunction, damage hippocampal and white matter integrity, and drive cognitive deficits after BCAS.
Methodology: The efficacy of SIK inhibition will be tested in aged VCID mice of both sexes. To establish
causality, Sik1/3 genes will be selectively knocked out in ECs or Mi/MΦ in young and aged mice. We will use a
battery of behavior tests, assessments of cerebral blood flow and BBB integrity, spatial transcriptomics at single-
cell resolution, and electrophysiological and histological assays for hippocampal structure and function.
Path to Translation and Implementation: A safe and optimized treatment regimen will be established in aged
mice of both sexes, to represent the elderly veteran population and set the stage for further preclinical testing
and translation to the veteran patient population. Fulfillment of the Aims will shed light on VCID pathophysiology
and hasten development of new therapies to directly benefit elderly veterans disabled by vascular dementia.

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