权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The physiologic and genomic relevance of mitoregulin in ischemic heart failure

线粒体调节蛋白在缺血性心力衰竭中的生理学和基因组相关性

基本信息

批准号：
10646411
负责人：
RYAN L BOUDREAU
金额：
$ 38.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646411
关键词：
3&apos Untranslated Regions Acute Address Affect American Apoptosis Apoptotic Area Arrhythmia Bioinformatics Biological Biology Blood flow Buffers Calcium Cardiac Cardiac Myocytes Cell Death Cell model Cells Cessation of life Clinical Data DNA Development Event Follow-Up Studies Future General Population Genes Genetic Genetic Markers Genetic Variation Genomics Genotype Goals Grant Healthcare Systems Heart Heart failure Hela Cells Human Human Genetics Hypoxia In Vitro Incidence Inner mitochondrial membrane Ischemia Knowledge Link Membrane Membrane Potentials Messenger RNA Metabolic Mitochondria Molecular Morbidity - disease rate Mus Muscle Myocardial Infarction Myocardial Ischemia Myocardium Names Necrosis Outcome Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Permeability Physiological Physiology Play Predisposing Factor Prevalence Production Protein Binding Domain Proteins Public Health Publishing RNA RNA-Binding Proteins Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Respiration Risk Risk Factors Rodent Rodent Model Role Sampling Testing Tissues Translating Treatment Failure Untranslated RNA Up-Regulation Variant Woman Work adverse outcome biological adaptation to stress cardioprotection cohort cost gain of function genetic variant high risk human disease improved ischemic cardiomyopathy knock-down loss of function men mitochondrial membrane mitochondrial permeability transition pore mortality multidisciplinary novel therapeutics overexpression prevent public health relevance respiratory response restoration

项目摘要

PROJECT SUMMARY / ABSTRACT Myocardial infarction (MI) is a primary cause of morbidity and mortality worldwide. Although reperfusion therapy improves post-MI survival, the rapid restoration of oxygenated blood flow to the heart elicits oxidative stress that further damages tissue, known as ischemia-reperfusion (IR) injury, exacerbating one’s risk for developing heart failure (HF). Central to IR injury are mitochondria, which play key roles in cardiomyocyte Ca2+ buffering and production of energy and reactive oxygen species (ROS). Upon IR, mitochondrial Ca2+ overload and ROS trigger mitochondrial permeability transition (mPT) pore opening, which promotes cell death. While many studies highlight the critical role of mPT in IR injury and cardioprotection, many molecular pathways leading to altered mitochondrial Ca2+ and ROS (key upstream regulators of mPT) remain poorly defined. In recent work, we discovered that a heart- and muscle- enriched long, “non-coding” RNA actually does encode for a highly-conserved single-pass transmembrane micro- protein that localizes to the inner mitochondrial membrane; we named this protein “Mitoregulin” (Mtln). In gain- and loss-of-function studies, we found that Mtln “supercharges” mitochondria by increasing their 1) respiratory super- complex levels, 2) respiratory efficiencies, and 3) Ca2+ retention capacities, while reducing ROS. In this grant, we propose Aims to address two central hypotheses: 1) that Mtln protects against cardiac IR injury by delaying Ca2+- and ROS-triggered mPT, and 2) that human genetic variation linked to Mtln expression associate with HF patient outcomes. Our overarching goal is to translationally link Mtln with cardiac IR injury and HF outcomes to justify a need for future studies to continue defining Mtln’s precise modes of action. In Aim 1, we will define the physiologic and molecular functions of Mtln in cardiomyocytes by evaluating the acute effects of modulating Mtln expression on mitochondrial respiration, Ca2+ and ROS, as well as supercomplex levels in cultured rodent cardiomyocytes. We will also define Mtln domains and protein interactions necessary for its function. In Aim 2, we will elucidate a role for Mtln in cell and rodent models of IR injury and HF through gain- and loss-of-function studies to evaluate the impact of Mtln modulation on cardiomyocyte death induced by simulated IR, as well as on responses to cardiac IR injury and ensuing HF in mice. In Aim 3, we will work to establish links among genetic variants, cardiac Mtln expression, and HF patient outcomes, focusing on the biological and genetic relevance of a 36-bp 3’UTR deletion variant (Mtln-3’UTRdel) that is present in 12% of the general population and is known to be linked to decreased Mtln mRNA levels in heart tissues. We will identify RNA-binding proteins that control Mtln expression and assess the impact of the 3’UTRdel variant on this regulation and on Mtln protein levels in human hearts. We will also test available DNA samples linked to clinical data in patient cohorts to assess the association of Mtln-3’UTRdel genotypes with HF incidence and outcomes (e.g. mortality and arrhythmic events). These multi-disciplinary studies have significant potential to 1) transform our knowledge of basic mitochondrial biology, 2) determine if Mtln represents a viable target for HF therapy, and 3) reveal new genetic markers that could translate towards improved identification and treatment of high-risk HF patients.

项目摘要/摘要

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.

DOI：
10.1128/mcb.00163-22
发表时间：
2022-10-20
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
通讯作者：

Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice.

DOI：
10.1161/jaha.122.025687
发表时间：
2022-07-05
期刊：
JOURNAL OF THE AMERICAN HEART ASSOCIATION
影响因子：
5.4
作者：
McLendon, Jared M.;Zhang, Xiaoming;Matasic, Daniel S.;Kumar, Mohit;Koval, Olha M.;Grumbach, Isabella M.;Sadayappan, Sakthivel;London, Barry;Boudreau, Ryan L.
通讯作者：
Boudreau, Ryan L.