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Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity

Award Number: K01HL145329
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity - Project Summary Traditionally, cardiotoxic effects in patients undergoing anthracycline-based chemotherapy (Anth-bC) are attributed to cardiomyocyte injury due to DNA damage and altered mitochondrial bioenergetics leading to excess reactive oxygen species and cell death. As a result, most research and treatment strategies are directed towards preventing cardiomyocyte injury. Recently, evidence from our group demonstrates that cardiac fibrosis also contributes to left ventricular dysfunction and heart failure symptoms following Anth-bC and now we have evidence that doxorubicin (Dox, a widely used Anth-bC) has a direct effect on cardiac fibroblasts to produce excess collagen. This project focuses on a candidate underlying mechanism by which Dox promotes cardiac fibroblasts activation and fibrosis: a stress response known as cellular senescence. Cellular senescence is characterized by permanent arrest of cell proliferation, mitochondrial dysfunction and development of a senescence-associated secretory phenotype (SASP) producing inflammatory cytokines, chemokines and proteases with both autocrine and paracrine effects. Although senescence has been studied in multiple cell types, there are virtually no data on senescence in adult cardiac fibroblasts. We have now evidence that cardiac fibroblasts exposed to Dox indeed develop mitochondrial dysfunction and become prematurely senescent. However, even in well studied cell types a complete understanding of the SASP secretome and the exact nature of the relationship between mitochondrial dysfunction and the senescence phenotype remain unclear. We propose to use isolated adult rat cardiac fibroblasts and a clinically relevant rat model of cardiotoxicity to critically determine the role of the secretome constituents in the activation of cardiac fibroblasts and the role mitochondrial dysfunction in the development of senescence and its association to cardiac fibrosis and left ventricular dysfunction. Our specific aims are designed to answer the following questions: 1) What are the proteomic constituents of the cardiac fibroblast secretome induced by Dox that stimulate a pro-fibrotic phenotype; 2) is there a causal role for mitochondria dysfunction in the development of Dox-induced senescence and SASP?; and 3) to what extent cardiac fibroblasts senescence, SASP and mitochondrial dysfunction are associated with the establishment and progression of myocardial fibrosis and LV dysfunction in vivo. Through the accomplishment of these significant aims, this project will train the PI in new areas of mass spectrometry-based proteomics, mitochondrial function and senescence biology. This training includes workshops in proteomics, experiential learning and development of leadership skills. Ultimately, this will lead to the success of her long term goal of becoming an independent funded investigator significantly contributing to the understanding of the molecular and cellular causes of the cardiovascular toxicities of chemotherapeutics that can be targeted to prevent and/or mitigate cardiovascular morbidities induced by these therapies.


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 = -$310 )
2024	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	5	6/25/2024	NON-COMPETING CONTINUATION	-$310
														Subtotal = -$310

Issue Date FY: 2023 ( Subtotal = $116,977 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	5	3/24/2023	NON-COMPETING CONTINUATION	$116,977
														Subtotal = $116,977

Issue Date FY: 2022 ( Subtotal = $118,382 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	4	3/10/2022	NON-COMPETING CONTINUATION	$118,382
														Subtotal = $118,382

Issue Date FY: 2021 ( Subtotal = $119,340 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	3	3/3/2021	NON-COMPETING CONTINUATION	$119,340
														Subtotal = $119,340

Issue Date FY: 2020 ( Subtotal = $114,162 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	2	3/3/2020	NON-COMPETING CONTINUATION	$114,162
														Subtotal = $114,162

Issue Date FY: 2019 ( Subtotal = $115,188 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	1	2/25/2019	NEW	$115,188
														Subtotal = $115,188

Grand Total All Awards = $583,739

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Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity

Award Number: K01HL145329

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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