Chromogranin A is an aging risk factor

项目摘要 嗜铬粒蛋白A（CgA）是内分泌和神经内分泌细胞的致密核心囊泡的组分， 控制神经递质和激素储存的神经元。CgA是一种激素原， 加工成具有独特生物功能的肽激素。这些肽中的两种，catestatin（CST： hCgA 352 -372）和胰抑素（PST：hCgA 250 -301），表现出完全相反的功能：CST是抗- 高血压、抗炎和抗糖尿病，而PST是促炎、促高血压和 促糖尿病高水平的CgA存在于患有恶性肿瘤、炎性肿瘤、淋巴瘤和淋巴瘤的患者的血液中。 疾病和神经系统疾病，其水平随着临床状况的恶化而上升。虽然Chga (gene编码CgA）-无效小鼠已经存在了近20年，并且已经被广泛研究， 尚未研究CgA对老化的影响。我们发现CgA-KO小鼠在高血压发生时， 年龄小，但在12个月大后会逆转。我们还注意到，一些未使用的CgA-KO小鼠（所有 男性）至少活了40个月。我们还发现脂蛋白脂酶的mRNA水平 (LPL)，其控制甘油三酯水平和V-set和含有免疫球蛋白结构域4（Vsig 4）， 通过自噬控制细菌清除，在CgA-KO年轻小鼠的心脏和肝脏中低，但在CgA-KO年轻小鼠的心脏和肝脏中高。 老老鼠我们进一步发现，细菌DNA泄漏到老年WT小鼠的其他不同器官。这些 初步观察提示，CgA是一种衰老诱导因子，但在早期有积极作用， 通过维持脂质代谢来延缓衰老。我们提出CgA到CST的差分处理 PST通过调节代谢和炎症因子来决定衰老。这 该提案旨在通过评估寿命，生长，线粒体 WT和CgA-KO男性和女性的较大队列的健康、能量消耗。我们将进一步 确定CgA诱导衰老的关键因素以及参与自发逆转的途径 CgA-KO小鼠的高血压和寿命延长，重点是脂蛋白-脂肪因子， 儿茶酚胺-肾上腺素能受体和Vsig-4-自噬信号轴。 这项拟议中的研究将由两名联合PI领导：Mahata博士，一位生理学家，他的研究重点是 研究高血压、胰岛素抵抗和免疫代谢的生物化学家戈什博士， 通过IKK-NF-κ B B信号通路调节炎症反应。如果假设被证明是正确的， 将进行长期研究以确定CgA诱导衰老的潜在机制。 这里提出的实验也将有助于确定CgA是否可以靶向治疗 炎症性疾病、衰老相关疾病和神经系统疾病， 以减少致病性的影响。

PROJECT SUMMARY Chromogranin A (CgA) is a component of dense core vesicles of endocrine and neuroendocrine cells and neurons that control the storage of neurotransmitters and hormones. CgA is a prohormone which is processed into peptide hormones with distinct biological functions. Two of these peptides, catestatin (CST: hCgA352-372) and pancreastatin (PST: hCgA250-301), exhibit diametrically opposite functions: CST is anti- hypertensive, anti-inflammatory, and anti-diabetic, whereas PST is pro-inflammatory, pro-hypertensive and pro-diabetic. High levels of CgA are present in the blood of patients with malignancies, inflammatory diseases, and neurological disorders, and their levels rise as their clinical conditions worsen. Although Chga (gene encoding CgA)-null mice have been available for nearly 20 years and have been widely studied, the impact of CgA on aging has not been investigated. We found that CgA-KO mice develop hypertension at a young age, but it reverses beyond the age of 12 months. We also noted that a few unused CgA-KO mice (all male) that were kept aside lived at least 40 months. We also found that mRNA levels of lipoprotein lipase (LPL), which controls triglyceride levels and V-set and immunoglobulin domain containing 4 (Vsig4), which control bacterial clearance via autophagy, are low in the heart and liver of CgA-KO young mice but high in old mice. We further found that leakage of bacterial DNA to other different organs in older WT mice. These preliminary observations imply that CgA is an aging-inducing factor, but it has a positive role at early ages through maintenance of lipid metabolism. We propose that differential processing of CgA into CST and PST would determine aging through regulation of factors involved in metabolism and inflammation. This proposal aims to investigate the validity of our hypothesis by assessing the lifespan, growth, mitochondrial health, energy expenditure of a larger cohort of WT and CgA-KO males and females. We will further determine the factors critical for CgA-induced aging and the pathways involved in the spontaneous reversal of hypertension and lifespan extension of CgA-KO mice with emphasis on the lipoprotein-adipokine, catecholamine-adrenergic receptor and Vsig-4-autophagy signaling axes in four different tissues. The proposed research will be led by two Co-PIs: Dr. Mahata, a physiologist whose research focuses on hypertension, insulin resistance and immunometabolism, and Dr. Ghosh, a biochemist who studies inflammatory responses through the IKK-NF-B signaling pathways. If the hypotheses prove to be correct, long-term studies to determine the underlying mechanisms of CgA-induced aging will be conducted. Experiments proposed here will also help to determine if CgA can be targeted for therapy against inflammatory disorders, aging-related and neurological disorders by lowering CgA transcripts at an older age to reduce the pathogenic repercussions.