NIH grant: Junctional mechanisms of HDAC7-mediated lung endothelial barrier regulation (1K99HL186240-01)

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NIH grant 1K99HL186240-01: Junctional mechanisms of HDAC7-mediated lung endothelial barrier regulation
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Rahul Shivaji Patil. Award: $136593.
Start: 2026-08-15T00:00:00.
PROJECT SUMMARY
Acute lung injury (ALI) is characterized by lung vascular endothelial cells (ECs) barrier compromise resulting in
EC permeability increase and pulmonary edema. Currently, there are no effective therapeutic options for ALI.
My novel preliminary data demonstrated that class IIa histone deacetylase, HDAC7 is upregulated in Human
Lung Microvascular ECs (HLMVECs) in response to lipopolysaccharide (LPS). Further, EC-specific deletion of
HDAC7 attenuates LPS-induced ALI in mice and HLMVEC barrier compromise suggesting a pro-edemagenic
role of EC HDAC7 expression in ALI. I found that the LPS increase in HDAC7 phosphorylation accompanied by
HDAC7 nuclear export. Phospho-HDAC7 retains in the cytoplasm where it may interact with extranuclear targets.
I observed that HDAC7 can specifically interact with phosphatase 2A (PP2A), which has a barrier-protective role
in ECs and required for maintaining functional EC junctions (ECJs). Further, PP2A is activated by hepatocyte
growth factor (HGF), which enhances EC barrier strengthening. However, the links between HGF-mediated
PP2A activation and HDAC7-mediated EC barrier regulation are not yet established. I demonstrated that HDAC7
interacts with ECJ proteins desmoplakin (DSP) and plakoglobin (PLN) suggesting a functional complex.
Interestingly, while LPS upregulates DSP, but not PLN, which accompanied by DSP phosphorylation/inhibition,
PP2A dephosphorylates it, suggesting re-activation. Further, depletion of DSP attenuates LPS-induced
HLMVEC permeability increase indicating the important role of DSP expression in LPS-induced EC barrier
compromise. However, these new findings raise important questions: (1) whether the extranuclear HDAC7 is
directly involved in the EC barrier compromise via inhibiting PP2A activity and rearrangement of ECJs; (2)
whether PP2A maintains EC junctional integrity and barrier protection through decreased HDAC7
phosphorylation; (3) mechanisms and functional significance of DSP expression modulation in EC barrier
regulation. Therefore, a primary goal of this project will be to define a novel role for HDAC7/DSP axis in the
PP2A-mediated ECJs rearrangement and barrier regulation. My preliminary data inform our overarching
hypothesis that the phosphorylation status of HDAC7 and its interaction with PP2A and its ECJ partners alter
intracellular signaling to regulate the EC barrier. To test this hypothesis, I propose the following specific aims.
K99 SA#1: To evaluate the role of HDAC7 phosphorylation/nuclear export in the LPS-induced ECJ-mediated
endothelial barrier compromise in vitro and in vivo. K99 SA#2: To determine the importance of PP2A-mediated
HDAC7 dephosphorylation in the assembly of ECJs and endothelial barrier strengthening in vitro and in vivo.
R00 SA#3: To evaluate the role of HDAC7/PP2A crosstalk in the regulation of desmoplakin expression in vitro
and in vivo. The conceptual and experimental training related to this proposal during the K99 phase will help me
pursue advanced topics in vascular biology as an independent investigator and position me well in applying for
my first R01 application.

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