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

Caspase-9 as a nodal point connecting necrotic and apoptotic cell death in myocardial infarction

Caspase-9作为连接心肌梗死细胞坏死和凋亡的节点

基本信息

批准号：
10666668
负责人：
Richard N Kitsis
金额：
$ 62.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666668
关键词：
ATP2A2 Adult Apoptosis Apoptotic Attenuated CASP3 gene CASP9 gene Cardiac Cardiac Myocytes Cell Death Cell Death Induction Cells Cessation of life Complex Data Drug Kinetics EFRAC Etiology Event Generations Genetic study Goals Heart Heart failure Infarction Inflammation Knockout Mice Knowledge Link Maps Mediating Molecular Mus Mutate Myocardial Infarction Myocardial Reperfusion Necrosis Nodal Oxidative Stress Pathway interactions Peptides Permeability Proteins Proteomics Regulation Reperfusion Therapy Resistance Role SERCA2a Series Signal Transduction Site Stroke Syndrome Testing Therapeutic Tissues apoptotic protease-activating factor 1 efficacy testing heart damage heart function in vivo inhibitor mortality mutant novel novel therapeutic intervention novel therapeutics programs rational design response therapy design x-linked inhibitor of apoptosis protein

项目摘要

The primary cardiac event in MI is cell death. Genetic studies in mice have established that most cardiomyocyte death during reperfused MI (MI/R) occurs through regulated cell death programs. This suggests that it should be possible in concept to limit cardiomyocyte death during MI/R to obtain the full benefit of reperfusion in maintaining cardiac function. A significant obstacle in achieving this goal, however, is that cardiomyocyte death in MI/R is mediated by several regulated apoptosis and necrosis programs, and the mechanisms that link these programs to produce an integrated cell death response remain poorly understood. This gap in knowledge has been a critical impediment for the rational design of therapies to limit cardiac damage during MI/R. Accordingly, a goal of our lab has been to understand the molecular framework that connects cell death programs in MI/R. Our preliminary studies have identified caspase-9 as an important link between apoptosis and necrosis programs during MI/R. The canonical role of caspase-9 in apoptosis is to activate downstream procaspases-3 and -7. However, we have identified a new pathway in which caspase-9 mediates cardiomyocyte necrosis during MI/R. In contrast to caspase-9-mediated apoptosis, caspases-3/7 are dispensable for caspase-9-mediated necrosis indicating the distinctness of the two pathways. However, as in apoptosis, caspase-9 enzymatic activity is required. To further dissect the pathway, we performed a proteomics-based screen for procaspase-9 interacting proteins in the heart during MI/R, which revealed proteins known to be involved in various aspects of necrosis. Thus far, we have focused on one procaspase-9 interactor, SERCA2a, which we hypothesize functions downstream of caspase-9 to mediate cell-intrinsic killing. Our data suggest that caspase-9 cleaves SERCA2a during MI/R disabling its function consistent with prior genetic studies showing that SERCA2a loss exacerbates cardiomyocyte necrosis and infarct size. We believe, however, that the relationship between procaspase-9 and SERCA2a is more complex. In addition to caspase-9 inducing SERC2a loss, our data suggest that SERCA2a loss may contribute to caspase-9 activation through Ca2+ overload. Thus, we hypothesize that a bidirectional mutually-reinforcing relationship exists between caspase-9 and SERCA2a and contributes to cardiomyocyte necrosis and infarct generation in MI/R. This project investigates critical aspects of the caspase-9-mediated necrosis pathway including activation mechanisms, downstream signaling, the relationship of the pathway to cell death programs thought to be involved in MI/R, and whether this pathway can be therapeutically inhibited to limit infarct size. Aim 1. To genetically dissect the caspase-9 necrosis axis during MI/R in vivo. Aim 2. To delineate the bidirectional regulation between caspase-9 and SERCA2A in cardiomyocyte necrosis during MI/R. Aim 3. To assess the therapeutic benefit of specifically inhibiting procaspase-9 during MI/R using a cell permeable peptide derived from an endogenous procaspase-9 inhibitor. These studies define a novel cell death pathway that appears important in MI/R and may provide the basis for a new therapeutic approach to limit infarct size.

心肌梗死的主要心脏事件是细胞死亡。对小鼠的遗传研究已经证实，大多数心肌细胞