Effect of Aging on Pancreatic Function

衰老对胰腺功能的影响

• 批准号: 7392159
• 负责人: Bernard Mark Evers
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7392159
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acinar Cell; Address; Affect; Age; Age-Years; Aging; Aging-Related Process; American; Caring; Cells; Collaborations; Data; Depth; Development; Disease; Doctor of Medicine; Elderly; Gene Expression; Genes; Genetic Models; Grant; Growth; Growth Factor; Health; Hormones; Impairment; Insulin-Like Growth Factor I; Laboratories; Lead; Life; Malignant Neoplasms; Mediating; Medical; Mus; North Carolina; Numbers; Organ; Pancreas; Pathway interactions; Pattern; Phosphatidylinositols; Physiological; Principal Investigator; Program Research Project Grants; Proteins; Published Comment; Rate; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Societies; Somatomedins; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Translating; Universities; age effect; age related; aged; base; body system; cell motility; clinically relevant; concept; day; design; gastrointestinal; in vitro Model; in vivo; innovation; novel; older patient; programs; receptor; receptor function; research study; response

Medical advances over the last century have enabled people to live longer and remain healthy for a significantly greater amount of time. It is critical that clinicians understand the changes that occur in various organ systems with aging if we are to achieve improvements in the care of the elderly patient. Significant alterations occur in the gastrointestinal (Gl) tract with aging, which can manifest as impairments in physiologic functions, such as alterations in growth, secretion, motility, and response to trophic factors. These changes have direct ramifications to diseases that are more common in the elderly, such as the development of Gl malignancies. Relatively few studies have rigorously examined the changes that occur in the Gl tract and pancreas with aging. With the support of this grant, our laboratory has made great strides in the better understanding of the physiologic changes that occur in the Gl tract with aging. We have identified important functional alterations that occur with age, such as dysregulation of pancreatic growth and function. Our studies have shown that aging affects Gl hormones and their target tissues. Recently, we have identified an important role for the phosphatidylinositol-3 kinase (PI3K) pathway in normal pancreatic proliferation; decreased PI3K/Akt activity is noted in the pancreas with aging, which is associated with decreased proliferative capacity. Based on our findings, the central hypothesis of this project is that aging results in a decreased proliferative capacity of the pancreas. Moreover, we postulate that a reduction in the activity of the PI3K/Akt signaling pathway contributes to the age-related changes possibly mediated by alteration in insulin-like growth factor-1 (IGF-1) expression or cell responsiveness to IGF-1. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) To determine the role of the PI3K/Akt pathway in the age-associated alteration of pancreatic growth. 2) To elucidate the role of IGF-1 and its receptor on altered PI3K/Akt expression and proliferation. 3) To further delineate alterations in the PI3K/Akt signaling pathway and upstream effector proteins in isolated acinar cells from young and aged pancreas. Our studies, utilizing novel in vivo and in vitro models, will continue to challenge previous concepts and viewpoints regarding the aging process. Finally, in collaboration with the other projects and cores in the Program Project Grant, our studies will continue to address clinically relevant questions of Gl health and disease with aging, which will translate to a better understanding of the effects of aging on the Gl tract and possibly lead to novel therapies.

上个世纪的医疗进步使人们的寿命更长，并且在更大的时间内保持健康。至关重要的是，如果我们要改善老年患者的护理，临床医生了解各种器官系统中发生的变化。随着衰老的胃肠道（GL）道，发生了重大变化，这可能表现为生理功能的损害，例如生长，分泌，运动性和对营养因素的反应的改变。这些变化对在老年人中更常见的疾病（例如GL恶性肿瘤的发展）产生了直接影响。相对较少的研究严格检查了随着衰老的gl段和胰腺发生的变化。在这笔赠款的支持下，我们的实验室在更好地理解随着衰老的GL区域的生理变化方面取得了长足的进步。我们已经确定了随着年龄的增长而发生的重要功能改变，例如胰腺生长和功能的失调。我们的研究表明，衰老会影响GL激素及其目标组织。最近，我们确定了正常胰腺增殖中磷脂酰肌醇-3激酶（PI3K）途径的重要作用。随着衰老的衰老，PI3K/AKT活性降低，这与增殖能力降低有关。根据我们的发现，该项目的核心假设是衰老导致胰腺增殖能力降低。此外，我们假设减少 PI3K/AKT信号通路的活性有助于与年龄相关的变化，这可能是由于胰岛素样生长因子1（IGF-1）表达的改变或对IGF-1的细胞反应性所介导的。为了审查这一假设，我们计划了以下特定目的的实验：1）确定PI3K/AKT途径在与年龄相关的胰腺生长变化中的作用。 2）阐明IGF-1及其受体对改变PI3K/AKT表达和增殖的作用。 3）进一步描述了来自年轻胰腺和老年胰腺的分离腺泡细胞中PI3K/AKT信号通路和上游效应蛋白的改变。我们利用体内和体外模型的新研究将继续挑战以前 有关老化过程的概念和观点。最后，与计划项目赠款中的其他项目和核心合作，我们的研究将继续解决与衰老有关的与临床相关的GL健康和疾病问题，这将改善人们对衰老对GL区域的影响的了解，并可能导致新的疗法。