Signaling Pathways in Dilated Cardiomyopathy

扩张型心肌病的信号通路

• 批准号: 9751939
• 负责人: Stephan Lange
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751939
• 关键词: Ablation; Actins; Adaptor Signaling Protein; Adrenergic Receptor; Animal Disease Models; Animal Model; Animals; Ankyrin Repeat; Biological; Biological Markers; Cardiac; Cardiomyopathies; Cell physiology; Chronic; Data; Development; Dilated Cardiomyopathy; Disease; Enzymes; Etiology; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heart; Heart failure; Human; Investigation; Knock-out; Knockout Mice; Lead; Link; Modeling; Modification; Morphology; Mus; Muscle; PRKCA gene; Pathologic; Pathology; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiology; Play; Post-Translational Protein Processing; Prevention; Program Development; Protein Family; Protein Kinase; Protein Kinase C; Proteins; Proteome; Proteomics; Publishing; Receptor Signaling; Research; Role; Sampling; Second Messenger Systems; Series; Signal Pathway; Study models; Testing; beta-adrenergic receptor; disorder prevention; human disease; in vivo; insight; knockout animal; member; mouse model; muscle LIM protein; new therapeutic target; phospholamban; programs; protein activation; public health relevance; receptor; skeletal; small molecule; transcription factor; transcriptome

 DESCRIPTION (provided by applicant): Much research has been devoted to delineate cardiac signaling pathways that lead to the development of dilated cardiomyopathy (DCM) and ultimately heart failure. Animal models, like the MLP/Csrp3 knockout that develops DCM have been used to delineate and identify specific pathways and pathway components involved in DCM development. Known pathway components include protein kinase Calpha, proteins involved in adrenergic receptor signaling, and phospholamban. Genetic ablation and/or small molecule inhibition of any of these components results in the prevention of DCM in MLP knockouts. Despite the insight that these studies and animal models provided, there is limited information of how these seemingly unconnected pathway components are linked, and whether as of yet unidentified components might play similar roles for DCM development. We found that MLP knockout mice when crossbred with the cardiac ankyrin repeat protein (CARP1/Ankrd1) knockout mice do not develop DCM. Preliminary investigations resulted in the hypothesis that pathological activation of a cardiac signaling pathway containing CARP1 and PKCalpha leads to the development of DCM in MLP knockout mice. We argue further that aberrant posttranslational modification of cardiac substrates for PKCalpha may be involved in the development of this disease. The overall goal of the proposed 5 year project is therefore to investigate and characterize protein substrates that are pathologically modified by PKCalpha, and identify CARP1 functions for the pathological modulation of the cardiac gene program and development of dilated cardiomyopathy. We aim to achieve these goals by investigating changes to the phospho-proteome using a proteomics approach. Specifically, posttranslational changes to proteins caused by aberrant kinase activity of PKCalpha observed in MLP mice will be analyzed. Further characterization of identified PKCalpha substrates will delineate disease relevant changes and their biological roles for the disease etiology. In addition, we are investigating the role of CARP1 for the pathological modulation of the cardiac gene program in MLP animals by a transcriptome analysis. We will further delineate whether CARP1 and PKCalpha play roles in DCM development beyond the MLP knockout mouse model, and in heart failure patients. Preliminary studies indicate that results from this project will further reine signaling pathways involved in DCM development and may lead to the identification of new therapeutic targets for the disease prevention.

 描述(由申请人提供)：许多研究都致力于描绘导致扩张型心肌病(DCM)发展和最终心力衰竭的心脏信号通路。动物模型，如发生DCM的MLP/Csrp3基因敲除，已被用来描述和识别参与DCM发展的特定途径和途径组件。已知的途径成分包括蛋白激酶Calpha、参与肾上腺素能受体信号转导的蛋白质和磷蛋白。基因消融和/或小分子抑制这些成分中的任何一个都可以预防MLP基因敲除中的DCM。尽管这些研究和动物模型提供了洞察力，但对于这些看似不相关的通路组件是如何联系在一起的，以及至今仍未确定的组件是否可能在DCM的发展中发挥类似的作用，信息有限。我们发现，当MLP基因敲除小鼠与心脏强直蛋白重复蛋白(CARP1/Ankrd1)基因敲除小鼠杂交时，不会发生DCM。初步研究结果表明，含有CARP1和PKCalpha的心脏信号通路的病理性激活导致MLP基因敲除小鼠发生DCM。我们进一步认为，心脏底物PKCalpha的异常翻译后修饰可能参与了这种疾病的发展。因此，拟议的5年计划的总体目标是调查和表征PKCalpha病理修饰的蛋白质底物，并确定CARP1在心脏基因程序的病理调节和扩张型心肌病发展中的功能。我们的目标是通过使用蛋白质组学方法研究磷酸蛋白质组的变化来实现这些目标。具体地说，将分析在MLP小鼠中观察到的PKCalpha蛋白激酶活性异常引起的蛋白质翻译后变化。对已鉴定的PKCalpha底物的进一步表征将描绘与疾病相关的变化及其在疾病病因学中的生物学作用。此外，我们正在通过转录组分析研究CARP1在MLP动物心脏基因程序的病理调控中的作用。我们将进一步阐明CARP1和PKCalpha是否在MLP基因敲除小鼠模型以外的DCM发展中发挥作用，以及在心力衰竭患者中发挥作用。初步研究表明，该项目的结果将进一步限制参与DCM发展的信号通路，并可能导致确定新的疾病预防治疗靶点。

项目成果

Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion.

• DOI: 10.1016/j.yjmcc.2018.07.248
• 发表时间: 2018-08
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Ehsan M;Kelly M;Hooper C;Yavari A;Beglov J;Bellahcene M;Ghataorhe K;Poloni G;Goel A;Kyriakou T;Fleischanderl K;Ehler E;Makeyev E;Lange S;Ashrafian H;Redwood C;Davies B;Watkins H;Gehmlich K
• 通讯作者: Gehmlich K

Challenges in PhD education due to COVID-19 - disrupted supervision or business as usual: a cross-sectional survey of Swedish biomedical sciences graduate students.

• DOI: 10.1186/s12909-021-02727-3
• 发表时间: 2021-05-22
• 期刊: BMC medical education
• 影响因子: 3.6
• 作者: Börgeson E;Sotak M;Kraft J;Bagunu G;Biörserud C;Lange S
• 通讯作者: Lange S

Exploring Obscurin and SPEG Kinase Biology.

• DOI: 10.3390/jcm10050984
• 发表时间: 2021-03-02
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Fleming JR;Rani A;Kraft J;Zenker S;Börgeson E;Lange S
• 通讯作者: Lange S

Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.

titin I波段中的单核苷酸多态性触发的病理机制的探索：心肌病连接的突变T2580i。

• DOI: 10.1098/rsob.160114
• 发表时间: 2016-09
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Bogomolovas J;Fleming JR;Anderson BR;Williams R;Lange S;Simon B;Khan MM;Rudolf R;Franke B;Bullard B;Rigden DJ;Granzier H;Labeit S;Mayans O
• 通讯作者: Mayans O

The N2A region of titin has a unique structural configuration.

• DOI: 10.1085/jgp.202012766
• 发表时间: 2021-07-05
• 期刊: The Journal of general physiology
• 作者: Stronczek C;Lange S;Bullard B;Wolniak S;Börgeson E;Mayans O;Fleming JR
• 通讯作者: Fleming JR