A family of novel mitochondrially-encoded peptides and their role in aging

描述（申请人提供）：一个新的线粒体编码肽家族及其在衰老中的作用摘要线粒体参与能量代谢和细胞凋亡，并且是多种疾病的中心，包括糖尿病、癌症和神经变性。线粒体含有数百种蛋白质，但染色体仅编码13种蛋白质。2001年，Humanin;一种新的24-氨基酸肽，编码自线粒体DNA的16 S核糖体RNA区域，被描述为一种有效的神经存活因子。几乎在同一时间，我们证明了humanin结合和拮抗促性腺激素分子IGFBP-3。在初步未发表的数据中，我们已经表明，humanin激活促生存信号级联，并证明它是一种有效的体内胰岛素增敏剂。我们最近发现，除了humanin，在16 S rRNA中还有六个额外的ORF，我们合成了相应的肽，我们将其命名为SHLP（small humanin-like peptides）。SHLPs 1-5的生物活性的初步表征表明，它们是有效的生物活性分子，其作用类似于humanin诱导细胞存活，但具有不同的时间分布，表明这些肽协同作用。SHLP-6具有相反的作用，抑制细胞生长。这些观察结果表明，线粒体可能具有以前未被认识到的作用，在调节代谢和生存发生通过合成的线粒体衍生肽（MDP）。线粒体染色体的生物信息学扫描表明，整个mtDNA中有超过100个额外的ORF。尤里卡奖项目旨在描述MDP的表达和特定功能，并尝试将MDP与衰老相关疾病的功能和遗传联系起来。我们的方法将涉及基因组学和蛋白质组学方法在人类与非凡的长寿和相关的小鼠模型的老化。我们认为线粒体肽组可以解释与衰老相关的线粒体生物学和功能障碍的重要新方面。这一系列研究是研究人员以前工作的一个巨大转变，代表了一个创新的高风险项目。所有国家，特别是美国，都在经历老年人口数量的增长。到2020年，世界老年人口预计将增加两倍，估计有7亿人年龄在65岁以上，其中70%将在发展中国家。特别重要的是，人口中最年长的老人人数增加，他们的医疗保健和其他需要传统上没有得到解决。改善老年人健康的机会有限。这是由于各种因素造成的：对老龄化的负面印象以及认为在老年人中促进健康和预防疾病不值得的概念;以及直到最近，研究界还忽视了老年人的共同问题。特别是衰老疾病，包括神经变性，代谢综合征和各种恶性肿瘤，影响大多数老年人，需要更好地了解所涉及的生物过程。最近的研究表明，生长因子是影响细胞存活和衰老的各种衰老相关过程的核心，并且已经提出了与生长因子相关的疗法作为解决衰老问题的可能方法。在我们提出的项目中，我们将研究一个新的生长和生存因子家族，称为SHLP，它似乎随着年龄的增长而下降，并可能代表治疗和诊断目标。

Description (provided by applicant): A family of novel mitochondrially-encoded peptides and their role in aging Abstract Mitochondria are involved in energy metabolism and apoptosis, and are central to multiple diseases, including diabetes, cancer, and neurodegeneration. Mitochondria contain hundreds of proteins, but the mitochondrial-chromosome only encodes 13 proteins. In 2001, humanin; a novel 24-amino-acid peptide encoded from the 16S ribosomal RNA region of the mtDNA, was described to be a potent neurosurvival factor. Almost at the same time we demonstrated that humanin binds and antagonizes the proapoptotic-molecule IGFBP-3. In preliminary unpublished data, we have shown that humanin activates a pro-survival signaling-cascade and demonstrated that it is a potent in vivo insulin sensitizer. We recently discovered that in addition to humanin, there are six additional ORFs within the 16S rRNA and we synthesized their corresponding peptides, which we named SHLPs (small humanin-like peptides). Initial characterization of the biological activity of the SHLPs 1-5 indicates that they are potent bioactive molecules acting to induce cell survival similarly to humanin, but with different temporal profiles, suggesting that these peptides act in concert. SHLP-6, has opposing actions, inhibiting cell growth. These observations suggest that the mitochondria may possess previously unappreciated roles in the regulation of metabolism and survival that occur via the synthesis of mitochondrial-derived peptides (MDPs). A bioinformatics scan of the mitochondrial chromosome indicates that there are over 100 additional ORFs throughout the mtDNA. This EUREKA Award project proposes to characterize the expression and specific functions of MDPs; and to try to functionally and genetically link MDPs to mitochondrially-related diseases of aging. Our approach will involve genomic and proteomic approaches in humans with exceptional longevity and in relevant mouse models of aging. We propose that the mitochondrial peptidome could explain important new aspects of mitochondrial biology and dysfunction with relevance to a aging. This line of research is a dramatic shift from the investigators previous work, and represents a innovative, high-risk project. of this research to public health All countries, and particularly the United States, are experiencing a growth in the numbers of elderly people in the population. By 2020 the world population of elderly people is expected to have trebled, with an estimated 700 million people aged 65 years and over of whom 70% will be in developing countries. Of particular significance is the growth of the oldest old in the population whose medical care and other needs have not been traditionally addressed. Opportunities for improving the health of elderly people have been limited. This is due to a variety of factors: negative images of ageing and concepts that health promotion and disease prevention in old age are not worthwhile; and, until relatively recently, neglect by the research community of common problems of old age. In particular diseases of aging, including neurodegeneration, metabolic syndrome, and various malignancies, affect the majority of the elderly and require a better understanding of the biological processes involved. Recent studies indicate that growth factors are central to various aging related processes affecting cell survival and senescence and growth factor related therapies have been proposed as possible approaches to the aging problem. In our proposed project we will study a family of novel growth and survival factors called SHLPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.