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A pilot study to define maintained alterations in mitochondrial DNA of eosinophilic esophagitis patients that may be exploited clinically

Award Number: R03AI156435
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/30/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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A pilot study to define maintained alterations in mitochondrial DNA of eosinophilic esophagitis patients that may be exploited clinically - Project Summary Eosinophilic Esophagitis (EoE) is a chronic, food antigen-mediated disease characterized by eosinophil-rich esophageal inflammation and symptoms such as abdominal pain, dysphagia and food impaction. A recent study identified damaging variants in the gene encoding the mitochondrial protein DHTKD1 in EoE patients. Although this indicates a potential role for mitochondria in EoE pathobiology, it remains unclear whether alterations in mitochondrial DNA are present in EoE and may be leveraged to improve clinical care of EoE patients. Indeed, mitochondria house reactive oxygen species (ROS)-producing electron transport chain components and have less sophisticated DNA repair mechanisms as compared to nuclear DNA, making mitochondria DNA highly susceptible to ROS-induced genetic alterations. This information in concert with our preliminary findings indicating (i) that there is an increase in mitochondria in esophageal epithelium of patients with active EoE that fails to normalize in inactive EoE patients; and (ii) mitochondrial dysfunction is induced in esophageal keratinocytes upon exposure to the EoE inflammatory milieu, led us to hypothesize that alterations in mitochondrial DNA may be acquired in esophageal mucosa of patients with Active EoE and maintained in a subset of Inactive patients in clinical disease remission. To test this hypothesis, we will pursue the following specific aims: Aim 1: Perform mitochondrial DNA sequencing in biopsy specimens from a cross-sectional cohort of human subjects comprising Normal controls as well as patients with Active and Inactive EoE. Gastroesophageal reflux disease patients will be evaluated to determine whether identified mitochondrial DNA alterations are specific to EoE. Aim 2: Perform mitochondrial DNA sequencing in biopsy specimens from a longitudinal cohort of human subjects comprising patients with tissues available at the time of both Active EoE and Inactive EoE and classified as therapeutic responders or non-responders. This study will (i) determine if mitochondrial DNA damage is a feature of EoE, both Active and Inactive; (ii) assess the relationship between mitochondrial DNA mutational burden and therapeutic response in EoE; and (iii) identify recurrent mitochondrial mutations that may be targeted therapeutically in EoE. Examples of potential mitochondria- targeted therapies for EoE include, delivery of antioxidant compounds (e.g. Coenzyme Q10) or micronutrients (e.g. Zinc, Biotin) to improve mitochondrial function, enzyme replacement therapy to restore the function of faulty enzymes encoded by mitochondrial DNA, and Adenoviral or CRISPR-mediated editing of the mitochondrial genome. Data generated in this study will provide the foundation for a future NIH R01 proposal that will delineate the functional significance of mitochondrial DNA alterations in EoE pathobiology and also evaluate therapeutic strategies related to mitochondrial dysfunction using preclinical models, including primary epithelial cultures, patient-derived esophageal organoids, and murine EoE models.


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: 2024 ( Subtotal = $0 )
2024	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	7/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	12/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $79,250 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	10/15/2021	NON-COMPETING CONTINUATION	$79,250
														Subtotal = $79,250

Issue Date FY: 2021 ( Subtotal = $79,250 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	11/30/2020	NEW	$79,250
														Subtotal = $79,250

Grand Total All Awards = $158,500

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A pilot study to define maintained alterations in mitochondrial DNA of eosinophilic esophagitis patients that may be exploited clinically

Award Number: R03AI156435

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/30/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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