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（申请人提供）：心肌细胞病理性肥大生长可导致心力衰竭；抑制这种生长可以避免心力衰竭。虽然我们对心脏的生长激活过程有很好的了解，但我们对生长抑制过程的理解还存在差距。该提案的目的是通过检查心肌细胞的肌浆/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，我们已经证明该系统可以调节心肌细胞的生长。这一目标与我们的长期目标一致，即制定通过减少病理性肥大来避免心力衰竭的创新策略。我们发现 SR/ER PQQC 系统的关键成员转录因子 ATF6 可减少心肌细胞肥大。 ATF6 也具有心脏保护作用，是一种感知生长信号的 SR/ER 跨膜 (TM) 蛋白。我们发现 ATF6 诱导 SR/ER TM E3 泛素 (Ub) 连接酶滑膜蛋白 (Syvn1)； SR/ER TM Ub 连接酶尚未在心脏中进行研究。令人惊讶的是，Syvn1 并不影响整体蛋白质泛素化或降解，但它减少了心肌细胞对生长刺激的肥大反应。假设 Syvn1 通过靶向 SR/ER 中产生的最终错误折叠蛋白质进行降解，从而减少有毒蛋白质错误折叠。此外，Syvn1 可以靶向选择性信号蛋白进行降解，例如胞浆生长促进激酶、血清/糖皮质激素调节激酶 1、SGK1，并且这些功能有助于 Syvn1 中度心脏肥大的能力。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小鼠心脏，以检查 Syvn1 功能获得和丧失的影响。具体目的是检查 Syvn1 功能获得或丧失对 1) 心脏肥大的影响，2) 心肌细胞肥大期间错误折叠的 SR/ER 蛋白的降解，以及 3) SGK1 及其对心肌细胞肥大的影响。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。这些结果将具有重要意义，因为它们将揭示抑制肥大的新机制，并将确定心力衰竭治疗的新靶点。拟议的研究具有创新性，因为尚未在任何组织中检查 SR/ER PQQC，特别是 SR/ER TM E3 Ub 连接酶在生长调节中的作用。