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的多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，是多种疾病的核心，包括糖尿病、癌症和神经退行性变。线粒体含有数百种蛋白质，但线粒体染色体只编码13种蛋白质。2001年，由线粒体DNA的16S核糖体RNA区域编码的一种新的24个氨基酸的多肽-人蛋白被描述为一种有效的神经生存因子。几乎在同一时间，我们证明了人素结合并拮抗促凋亡分子IGFBP-3。在尚未发表的初步数据中，我们已经表明人素激活了促进生存的信号级联，并证明了它是体内有效的胰岛素增敏剂。我们最近发现，除了人蛋白外，在16S rRNA中还存在另外6个ORF，我们合成了相应的多肽，我们将其命名为SHLPs(小的人蛋白样多肽)。对SHLP 1-5生物活性的初步表征表明，它们是类似于人的诱导细胞存活的有效生物活性分子，但具有不同的时间分布，表明这些多肽是协同作用的。SHLP-6具有相反的作用，抑制细胞生长。这些观察表明，线粒体可能具有以前未被认识的作用，通过合成线粒体衍生多肽(MDP)来调节新陈代谢和生存。对线粒体染色体的生物信息学扫描表明，整个线粒体DNA中有100多个额外的ORF。这个尤里卡奖项目建议描述MDP的表达和特定功能；并试图从功能和基因上将MDP与线粒体相关的衰老疾病联系起来。我们的方法将涉及人类的基因组和蛋白质组方法，以及相关的衰老小鼠模型。我们认为，线粒体多肽组可以解释线粒体生物学和与衰老相关的功能障碍的重要新方面。这条研究路线与调查人员以前的工作相比是一个戏剧性的转变，代表着一个创新的、高风险的项目。在这项对公共卫生的研究中，所有国家，特别是美国，都在经历人口中老年人数量的增长。到2020年，世界老年人口预计将翻两番，估计将有7亿65岁及以上的人口，其中70%将在发展中国家。特别重要的是人口中年龄最大的老年人的增长，他们的医疗保健和其他需求在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和认为老年时促进健康和预防疾病不值得的观念；以及直到最近，研究界对老年常见问题的忽视。特别是老年病，包括神经退行性变、代谢综合征和各种恶性肿瘤，影响着大多数老年人，需要更好地了解相关的生物过程。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，与生长因子相关的治疗已被提出为解决衰老问题的可能途径。在我们提出的项目中，我们将研究一类新的生长和生存因素，称为SHLP，它似乎随着年龄的增长而下降，可能是治疗和诊断的靶点。

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 In preliminary unpublished data, we have shown that humanin activates a pro-survival signaling-cascade and demonstrated that it is a potent in vivo insulin sensitizer.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.