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New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation

Award Number: R35HL161249
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation - PROJECT SUMMARY Atrial fibrillation (AF) is the most common heart rhythm disorder that affects >3 million Americans and is a major cause of stroke. Since AF is primarily an age-related disease, it is fast becoming an epidemic in a rapidly aging population. Unfortunately, current therapeutic approaches to AF – both pharmacological and ablation- based - are sub-optimal in patients with persistent AF. This is thought to be because current treatments do not target the fundamental, molecular mechanisms that cause AF. Over the last several years, the Arora lab at Northwestern University has worked hard to better understand the molecular mechanisms underlying AF, with the long term goal of developing a mechanism-guided therapeutic approach to AF. Work done in the Arora lab over the last several years in large animal models of AF has demonstrated that autonomic nervous system signaling, oxidative injury and CAMKII signaling are important mechanisms leading to electrical remodeling of key ion channels and excitation contraction coupling proteins in the atrium, thereby leading to the establishment of substrate for paroxysmal AF. The goal of the Arora lab over the next several years is to obtain a better understanding of the molecular mechanisms that underlie the progression of paroxysmal AF to persistent AF. We postulate that structural changes in the atrium such as new parasympathetic nerve sprouting, NLRP3 inflammasome mediated fibrosis and HDAC6 mediated breakdown of microtubules (derailed proteastasis) are key mechanisms underlying this progression of AF. We will study these mechanisms in chronically tachypaced large animal models of AF by using novel gene therapy approaches developed in our lab over the last several years. Success of these gene therapy approaches in arresting progression of paroxysmal AF to persistent AF will also demonstrate their therapeutic potential. Since our eventual goal is to develop a clinically viable gene therapy approach for persistent AF, we have recently conceived of a highly novel electroporation-based approach to facilitate trans-venous gene delivery. In addition to identifying novel gene therapy targets for AF, another major goal of this R35 proposal will be to fully develop and optimize this gene delivery approach. The next phase of the research proposed in the Arora lab is not only expected to give fresh mechanistic insights into the creation of an atrial myopathy that supports persistent AF, but is also expected to led to the development of new, potentially paradigm-shifting therapeutic approaches to AF.


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: 2026 ( Subtotal = $0 )
2026	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	3	4/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $984,000 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cardiovascular Diseases Research	002	4	6/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$984,000
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	3	6/16/2025	NON-COMPETING CONTINUATION	$0
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	11/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $984,000

Issue Date FY: 2024 ( Subtotal = $940,799 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	3	12/18/2023	NON-COMPETING CONTINUATION	$863,999
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$76,800
														Subtotal = $940,799

Issue Date FY: 2023 ( Subtotal = $960,000 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$960,000
														Subtotal = $960,000

Issue Date FY: 2022 ( Subtotal = $960,000 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	1	1/20/2022	NEW	$960,000
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	1	8/5/2022	NEW	$0
														Subtotal = $960,000

Grand Total All Awards = $3,844,799

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New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation

Award Number: R35HL161249

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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