Chromogranin A is an aging risk factor

嗜铬粒蛋白 A 是衰老的危险因素

基本信息

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
项目类别：
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&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目概要嗜铬粒蛋白 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，控制神经递质和激素储存的神经元 CgA 是一种激素原。加工成具有不同生物功能的肽激素，其中两种肽是儿茶素（CST：）。 hCgA352-372) 和胰酶 (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 则促炎、促高血压和恶性肿瘤、炎症患者的血液中存在高水平的 CgA。疾病和神经系统疾病，其水平随着临床状况恶化而升高。 (基因编码CgA)缺失小鼠问世已近20年，并已得到广泛研究，我们尚未研究 CgA 对衰老的影响。我们发现 CgA-KO 小鼠在一定时间内会出现高血压。年轻时，但超过 12 个月后，我们还注意到一些未使用的 CgA-KO 小鼠（全部）。男性）被放在一边至少活了 40 个月，我们还发现脂蛋白脂肪酶的 mRNA 水平。 (LPL)，控制甘油三酯水平，V-set 和含有 4 (Vsig4) 的免疫球蛋白结构域，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 CgA-KO 幼鼠的心脏和肝脏中含量较高我们进一步发现老年 WT 小鼠的细菌 DNA 渗漏到其他不同的器官。初步观察表明CgA是一种诱发衰老的因素，但它对早期衰老有积极作用。我们建议将 CgA 差异加工成 CST。 PST 会通过调节参与代谢和炎症的因素来决定衰老。该提案旨在通过评估寿命、生长、线粒体来调查我们假设的有效性我们将进一步研究更多 WT 和 CgA-KO 男性和女性群体的健康、能量消耗。确定 CgA 诱导衰老的关键因素以及参与自发逆转的途径高血压和 CgA-KO 小鼠寿命延长，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受体和 Vsig-4 自噬信号轴。拟议的研究将由两位联合 PI 领导： Mahata 博士，一位生理学家，其研究重点是高血压、胰岛素抵抗和免疫代谢方面的研究，以及生物化学家 Ghosh 博士的研究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 是否可以作为治疗的目标通过在老年时降低 CgA 转录本来治疗炎症性疾病、衰老相关疾病和神经系统疾病以减少致病影响。