Roles for SR/ER Protein Quantity and Quality Control in Cardiac Hypertrophy

SR/ER 蛋白数量和质量控制在心脏肥大中的作用

• 批准号: 8916213
• 负责人: Chris Glembotski
• 金额: $ 37.5万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2015-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916213
• 关键词: Address; Affect; Atrophic; Attenuated; Cardiac; Cardiac Myocytes; Cell Nucleus; Cell physiology; Cessation of life; Data; Development; Disease; Endoplasmic Reticulum; Equilibrium; Future; Gene Expression; Gene Transfer; Genes; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Histocompatibility Testing; Hypertrophy; Innovative Therapy; Integral Membrane Protein; Lead; Life; Location; Malignant Neoplasms; Mediating; Mission; Molecular; Mus; Myocardial; Pathology; Pathway interactions; Phosphotransferases; Process; Protein Biosynthesis; Proteins; Public Health; Quality Control; Regulation; Research; Role; Sgk protein; Signal Transduction; Signaling Protein; Stimulus; Symptoms; System; Thinking; Tissues; Ubiquitin; Ubiquitination; United States National Institutes of Health; Viral; cell growth; cell type; constriction; heart dimension/size; in vivo; innovation; loss of function; member; mouse model; novel; overexpression; pressure; protein degradation; protein folding; protein metabolism; protein misfolding; response; transcription factor ATF6; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Pathological hypertrophic growth of cardiac myocytes can lead to heart failure; inhibiting this growth can avert heart failure. While we have a good understanding of growth-activating processes in the heart, there is a gap in our understanding of growth-inhibiting processes. The objective of this proposal is to address this gap by examining the protein quantity and quality control (PQQC) system in the sarco/endoplasmic reticulum (SR/ER) of cardiac myocytes, which we have shown can moderate cardiac myocyte growth. This objective aligns with our long-term goal of defining innovative strategies for averting heart failure by reducing pathological hypertrophy. We found that a key member of the SR/ER PQQC system, the transcription factor, ATF6, decreases cardiac myocyte hypertrophy. ATF6, which is also cardioprotective, is an SR/ER transmembrane (TM) protein that senses growth signals. We showed that ATF6 induces the SR/ER TM E3 ubiquitin (Ub) ligase, synoviolin (Syvn1); SR/ER TM Ub ligases have not been studied in the heart. Surprisingly, Syvn1 did not affect global protein ubiquitination or degradation, but it decreased cardiac myocyte hypertrophy in response to growth stimuli. The hypothesis is that Syvn1 decreases toxic protein misfolding by targeting terminally misfolded proteins made in the SR/ER for degradation. Moreover, Syvn1 can target select signaling proteins for degradation, such as the cytosolic growth-promoting kinase, serum/glucocorticoid-regulated kinase 1, SGK1, and that these functions contribute to the ability of Syvn1 to moderate cardiac hypertrophy. The approach will use viral-mediated gene transfer to cultured cardiac myocytes and to mouse hearts, in vivo, to examine the effects of Syvn1 gain- and loss-of-function. The specific aims are to examine the effects of Syvn1- gain- or loss-of-function on 1) cardiac hypertrophy, 2) the degradation of misfolded SR/ER proteins during cardiac myocyte hypertrophy, and 3) the level, location and activity of SGK1, and its impact on cardiac myocyte hypertrophy. The proposed studies are expected to show that, as a regulator of PQQC, Syvn1 contributes to balancing protein synthesis and protein folding capacity. These results will be significant because they will reveal novel mechanisms of inhibiting hypertrophy, and they will identify new targets for HF therapy. The proposed research is innovative because roles for the SR/ER PQQC and, specifically, SR/ER TM E3 Ub ligases in growth regulation have not been examined in any tissue.

描述（由申请人提供）：心肌细胞的病理肥厚性生长会导致心力衰竭；抑制这种生长会避免心力衰竭。虽然我们对心脏中的成长激活过程有很好的了解，但我们对抑制生长过程的理解存在差距。该提案的目的是通过检查心肌细胞的肌肉/内质网（SR/ER）中的蛋白质数量和质量控制（PQQC）系统来解决这一差距，我们表明，这可能会中度心肌细胞生长。该目标符合我们的长期目标，即通过减少病理肥大来定义避免心力衰竭的创新策略。我们发现SR/ER PQQC系统的关键成员ATF6的转录因子降低了心肌细胞肥大。也是心脏保护的ATF6是一种感受生长信号的SR/ER跨膜（TM）蛋白。我们表明ATF6诱导SR/ER TM E3泛素（UB）连接酶，Synoviolin（SyVN1）；尚未在心脏中研究SR/ER TM UB连接酶。令人惊讶的是，SYVN1不影响全球蛋白质泛素化或降解，但它响应生长刺激而降低了心肌肥大。假设是SYVN1通过靶向SR/ER中的终末错误折叠蛋白来降低毒性蛋白质折叠率，以降解。此外，SYVN1可以靶向选择的信号蛋白进行降解，例如胞质生长激酶，血清/糖皮质激素调节的激酶1，SGK1，这些功能有助于Syvn1的能力，使SYVN1能够对中度心动ac症的中度心脏肥大。该方法将使用病毒介导的基因转移到培养的心肌细胞和体内的小鼠心脏，以检查SYVN1的功能丧失和功能丧失的作用。具体的目的是检查SYVN1-功能丧失对1）心脏肥大的影响，2）心肌肌细胞肥大期间错误折叠的SR/ER蛋白的降解以及3）SGK1的水平，位置和活动及其对心脏肌细胞肥大的影响。拟议的研究预计将表明，作为PQQC的调节剂，SYVN1有助于平衡蛋白质合成和蛋白质折叠能力。这些结果将很重要，因为它们将揭示抑制肥大的新型机制，并将确定HF治疗的新靶标。拟议的研究具有创新性，因为SR/ER PQQC的作用，特别是在生长调节中的SR/ER TM E3 UB连接酶，尚未在任何组织中检查。