Chromogranin A is an aging risk factor

嗜铬粒蛋白 A 是衰老的危险因素

• 批准号: 10667265
• 负责人: GOURISANKAR GHOSH
• 金额: $ 22.97万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667265
• 关键词: Adipose tissue; Adrenergic Receptor; Age; Aging; Alzheimer' s disease brain; Alzheimer' s disease patient; Anti-Inflammatory Agents; Antidiabetic Drugs; Antihypertensive Agents; Antioxidants; Autoimmune Diseases; Autophagocytosis; Bacterial DNA; Biochemical; Biological Process; Blood; Blood Glucose; Blood Pressure; Blood Vessels; Cardiac; Catecholamines; Cells; Cessation of life; Characteristics; Cholesterol; Chromogranin A; Chronic; Clinical; Collaborations; Communication; Coupled; Data; Dense Core Vesicle; Development; Diabetes Mellitus; Disease; Eating; Elderly; Endocrine; Energy Metabolism; Exhibits; Extravasation; Fatty Acids; Female; Future; Gene Expression; Gene Expression Profiling; Genes; Goals; Growth; Health; Heart; Heart failure; Hormones; Hypertension; Immunoglobulin Domain; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insulin; Insulin Resistance; Intestinal permeability; Kidney Failure; Knock-out; Knockout Mice; Life; Lipoproteins; Liver; Liver Dysfunction; Longevity; Longitudinal Studies; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; Mitochondria; Modeling; Mus; Muscle; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Neurotransmitters; Norepinephrine; Organ; Pathogenicity; Pathway interactions; Patients; Peptides; Physiological; Physiology; Plasma; Process; Proteins; Proteolytic Processing; Publishing; Regulation; Reporting; Research; Respiration; Rheumatoid Arthritis; Risk Factors; Role; SET Domain; Signal Pathway; Signal Transduction; Testing; Tissue Sample; Tissues; Transcript; Triglycerides; Tumor Suppressor Proteins; Wild Type Mouse; adipokines; adiponectin; age group; age related; aged; blood pressure elevation; cohort; diabetic; experimental study; human old age (65+); hypertensive; improved; insulin sensitivity; lipid metabolism; lipoprotein lipase; male; mature animal; mouse model; nervous system disorder; overexpression; pancreastatin; peptide hormone; prohormone; resistance gene; targeted treatment; transcriptome sequencing

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.

项目摘要 促炎A（CGA）是内分泌和神经内分泌细胞的密集核心蔬菜的组成部分 控制神经递质和激素的存储的神经元。 CGA是一种激素 加工成具有不同生物学功能的肽恐怖。这些肽中的两个是catestatin（CST： HCGA352-372）和胰腺蛋白（PST：HCGA250-301），暴露于直径相反的功能：CST是抗 高血压，抗炎和抗糖尿病患者，而PST具有促炎，促疾病 亲糖尿病。恶性，炎症患者的血液中存在高水平的CGA 疾病和神经系统疾病及其水平随临床状况恶化而升高。虽然cha （编码CGA的基因） - 无小鼠已有近20年的时间，并且已被广泛研究， 尚未研究CGA对衰老的影响。我们发现CGA-KO小鼠在A处出现高血压 年轻，但它逆转超过12个月的年龄。我们还注意到一些未使用的CGA-KO小鼠（全部 被搁置的男性）至少有40个月的生活。我们还发现脂蛋白脂肪酶的mRNA水平 （LPL）控制甘油三酸酯水平以及含4（VSIG4）的V-stet和免疫球蛋白结构域，它们 通过自噬的对照细菌清除率，CGA-KO幼鼠的心脏和肝脏较低，但很高 老鼠。我们进一步发现，细菌DNA泄漏到较老的WT小鼠中其他不同器官。这些 初步观察表明，CGA是老化引起的因素，但在早期起着积极的作用 通过维持脂质代谢而老化。我们建议将CGA的差分处理到CST PST将通过调节代谢和注射涉及的因素来确定衰老。这 提案旨在通过评估寿命，生长，线粒体来研究我们假设的有效性 较大的WT和CGA-KO男性和女性的健康，能量消耗。我们将进一步 确定CGA诱导的衰老和涉及的途径至关重要的因素 CGA-KO小鼠的高血压和寿命延伸，重点是脂蛋白 - 磷灰胺 在四个不同组织中的儿茶酚胺 - 肾上腺素受体和VSIG-4-噬轴信号轴。 拟议的研究将由两位共同提议主持：生理学家Mahata博士的研究重点 关于高血压，胰岛素抵抗和免疫代谢，以及研究的生物化学家Ghosh博士 通过IKK-NF-B信号通路发出的炎症反应。如果假设被证明是正确的， 将进行长期研究以确定CGA诱导的衰老的潜在机制。 此处提出的实验还将有助于确定CGA是否可以针对治疗 通过降低CGA成绩单，炎症性疾病，与衰老有关的疾病和神经系统疾病 减少致病性影响。