Chromogranin A is an aging risk factor

项目总结 嗜铬粒蛋白A(CGA)是内分泌和神经内分泌细胞致密核心囊泡的组成部分， 控制神经递质和荷尔蒙储存的神经元。CGA是一种前激素，它是 加工成具有不同生物功能的多肽激素。其中两种多肽，儿茶素(CST： HCgA352-372)和胰腺抑素(PST：hCgA250-301)表现出截然相反的功能：CST是抗 高血压、抗炎和抗糖尿病，而PST是促炎、促高血压和 糖尿病患者。恶性肿瘤、炎症性疾病患者血液中存在高水平的CgA 疾病和神经紊乱，它们的水平随着临床情况的恶化而上升。尽管Chga (编码CGA)基因缺失的小鼠已经存在了近20年，并得到了广泛的研究， CGA对衰老的影响尚未被研究。我们发现CGA-KO小鼠在 年龄很小，但超过12个月后就会逆转。我们还注意到，一些未使用的CGA-KO小鼠(均为 男性)，放在一边至少活了40个月。我们还发现，脂蛋白脂酶的mRNA水平 (LPL)，它控制甘油三酯水平和V-SET和含有4(Vsig4)的免疫球蛋白结构域，它 通过自噬控制细菌清除，在CGA-KO幼鼠的心脏和肝脏中含量较低，但在 老老鼠。我们进一步发现，在老年WT小鼠中，细菌DNA泄漏到其他不同的器官。这些 初步观察表明，CGA是一种衰老诱导因素，但在早期有积极的作用 AGEs通过维持脂类代谢。我们建议将CGA的差异处理为CST 而PST将通过调节涉及代谢和炎症的因素来决定衰老。这 该提案旨在通过评估寿命、生长、线粒体 WT和CGA-KO男性和女性的健康、能量消耗较大的队列。我们将进一步 确定CGA诱导衰老的关键因素和参与自发逆转的途径 高血压和延长CGA-KO小鼠寿命的研究，重点是脂蛋白-脂肪因子， 四种不同组织中的儿茶酚胺-肾上腺素能受体和VSIG-4-自噬信号轴。 这项拟议的研究将由两名合作PI领导：Mahata博士，他是一名生理学家，其研究重点是 关于高血压、胰岛素抵抗和免疫新陈代谢的研究，以及戈什博士，他是一名生物化学家，研究 炎症反应通过IKK-NF-B信号通路。如果这些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是否可以作为治疗的靶点。 炎症性疾病、衰老相关疾病和神经系统疾病--通过降低老年CGA转录本 以减少致病反应。

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.