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A Novel Approach to Target Neutrophilic Airway Inflammation and Airway Hyperresponsiveness in Therapy-Resistant (Refractory) Asthma.

Award Number: R01HL164593
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Airway hyperresponsiveness (AHR) and airway inflammation are hallmarks of asthma. Refractory asthma manifests with persistent symptoms despite use of high-dose oral corticosteroids and long-acting ß2-agonist bronchodilators and poses a major healthcare challenge. Understanding the mechanisms and developing strategies to overcome therapeutic resistance poses a significant unmet need. Airway smooth muscle (ASM) hypercontraction is a key factor of AHR, and T-helper 17 (Th17) cells promote steroid-insensitive neutrophilic airway inflammation (NAI). We found p63RhoGEF, a RhoA activator, plays crucial roles in refractory asthma. We also developed CXN-8, a small molecule inhibitor of p63RhoGEF. Objective: To determine the importance and mechanisms by which p63RhoGEF modulates the asthma diathesis and if CXN-8 inhibits p63RhoGEF to ameliorate AHR and NAI. Long-term goal: To develop new therapies for refractory asthma. Findings: 1) p63- RhoGEF is selectively upregulated in asthmatics and plays a critical role in RhoA activation that controls ASM hypercontraction and Th17 cell differentiation. 2) CXN-8 inhibits ASM contraction and induces relaxation of airway. 3) CXN-8 ameliorates AHR and NAI in murine asthma models. 4) CXN-8 interacts with p63RhoGEF to block RhoA activation. Hypothesis: Targeting p63RhoGEF-stimulated ASM hypercontractility and Th17 cell differentiation with CXN-8 ameliorates AHR and NAI and that CXN-8 therapy represents a novel strategy for refractory asthma. We will test this hypothesis in vitro and in vivo. Aim 1. To define the mechanism underlying p63RhoGEF and CXN-8 regulation of AHR. We will use RNAi and inhibitors to determine the pivotal role and mechanism of p63RhoGEF in hypercontractility of asthmatic human ASM (HASM) cells. We will analyze CXN- 8 regulation of RhoA activity, Ca2+ signaling, contraction/relaxation of ß2-agonist-sensitive/insensitive HASM cells. We will combine RNAi, mutagenesis, and surface plasmon resonance to elucidate the specificity and mechanism for CXN-8 regulation of p63RhoGEF. Whether p63RhoGEF loss ameliorates AHR and reduces the effects of CXN-8 will be examined in a house dust mite (HDM)-driven murine model of asthma. Aim 2. To elucidate the mechanism underlying p63RhoGEF and CXN-8 regulation of NAI. We will examine the effects of CXN-8 on Th17 cell differentiation. We will silence RhoA or express an active RhoA mutant to establish its importance in CXN-8 inhibition of Th17 cell differentiation. We will also determine if loss of p63RhoGEF attenuates RhoA activation and Th17 differentiation in cells and HDM-induced NAI in mice and reduces CXN-8 inhibitory effects in vitro and in vivo. Aim 3. To examine the therapeutic potential of CXN-8 in murine models of refractory asthma. We will determine if inhaled CXN-8 is an acute and effective bronchodilator in a murine model of ß2-agonist insensitive AHR. We will test lung targeted, long-acting CXN-8 microparticles to alleviate AHR/NAI with limited systemic side-effects in a murine model of corticosteroid-insensitive asthma. The impact of p63RhoGEF loss on AHR/NAI and therapeutic effects of CXN-8 will also be examined in these studies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $411,112 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Lung Diseases Research	000	1	8/29/2023	NEW	$411,112
														Subtotal = $411,112

Grand Total All Awards = $411,112

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A Novel Approach to Target Neutrophilic Airway Inflammation and Airway Hyperresponsiveness in Therapy-Resistant (Refractory) Asthma.

Award Number: R01HL164593

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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