Novel Mitochondrially Encoded Peptides and Their Role in Health and Disease

描述（申请人提供）：疾病中线粒体的功能变异线粒体参与能量代谢和细胞凋亡，含有近千种蛋白质，其中大部分由核基因组编码。线粒体染色体以前被认为只编码13种蛋白质，主要作为线粒体电子传递链的组成部分。线粒体功能障碍与许多疾病有关，包括神经发育、糖尿病和癌症，尽管其在这些疾病发展中的确切作用仍存在争议。在2001年，humanin，一个24个氨基酸的肽，建议从线粒体DNA的16 S核糖体RNA编码，被描述为一个强大的神经生存因子，我们最近已经表明，它是一个集中作用在体内胰岛素增敏剂。我们最近发现，除了humanin之外，16 S rRNA内还有六个ORF，我们合成了相应的肽，我们将其命名为SHLP（small humanin-like peptides）。SHLP 1 -5有效地诱导细胞存活类似于humanin，但具有不同的时间曲线，表明这些肽可能协同作用。SHLP 6具有相反的作用，抑制肿瘤生长和血管生成。因此，我们建议的范式转移假说，线粒体发挥了以前不受重视的作用，在细胞和生物体的功能，通过生产的神经衍生肽（MDP）的调节。该项目有几个目标：1）鉴定和验证其他新的MDP; 2）确定MDP来自线粒体与NUMT/核来源的来源; 3）表征MDP的细胞内运输; 4）评估MDP对细胞生物学和体内生理学的影响; 5）将MDP确立为人类疾病的治疗和诊断靶标。我们认为，Humanin和SHLP是许多MDPs中的第一个。这些肽可以迅速成为与线粒体功能障碍相关的疾病的潜在诊断和治疗靶点，包括神经退行性疾病，糖尿病和癌症。因此，我们认为线粒体不仅是能量产生和促凋亡的细胞器，而且是重要的生物活性肽的来源，这些MDP的失调在疾病发展中很重要。 公共卫生相关性：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，老年人的疾病主要是癌症、阿尔茨海默病和糖尿病综合征，所有这些都与线粒体功能障碍有关。改善这些人健康的机会有限。这是由于各种因素造成的：对老龄化的负面印象以及认为老年人不值得促进健康和预防疾病的概念;直到最近，研究界还忽视了老年人的常见问题，而这些问题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，并且已经提出了生长因子相关疗法作为解决衰老问题（包括糖尿病和阿尔茨海默氏病）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MDP，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): Functional Variation in Mitochondria in Disease Mitochondria are involved in energy metabolism and apoptosis, and contain nearly a thousand proteins, most of which are encoded by the nuclear genome. The mitochondrial chromosome was previously though to encode only 13 proteins that function primarily as components of the mitochondrial electron transport chain. Mitochondrial dysfunction has been associated with many diseases, including neurogegeneration, diabetes and cancer, although its exact role in the development of these diseases remains controversial. In 2001, humanin, a 24-amino-acid peptide proposed to be encoded from the 16S ribosomal RNA of the mtDNA, was described as a potent neurosurvival factor, and we have recently shown it to be a centrally acting in vivo insulin sensitizer. We recently discovered that in addition to humanin, there are six ORFs within the 16S rRNA, and we synthesized the corresponding peptides, which we named SHLPs (small humanin-like peptides). SHLP1-5 potently induce cell survival similarly to humanin, but with different temporal profiles, suggesting that these peptides may act in concert. SHLP6 has opposing actions, inhibiting tumor growth and angiogenesis. We therefore suggest the paradigm-shifting hypothesis that mitochondria play a previously unappreciated role in the regulation of cellular and organismal function through the production of mitochondrial-derived peptides (MDPs). This project has several goals: 1) Identify and verify additional novel MDPs; 2) Define the source of MDPs from mitochondrial versus NUMT/nuclear origin; 3) Characterize the intracellular trafficking of MDPs; 4) Assess the effect of MDPs on cell biology and in vivo physiology; 5) Establish MDPs as therapeutic and diagnostic targets in human disease. Humanin and SHLPs are, we believe, the first of many MDPs. These peptides could rapidly emerge as potential diagnostic and therapeutic targets for diseases associated with mitochondrial dysfunction, including neurodegenerative diseases, diabetes and cancer. We therefore propose that mitochondria are not simply energy production and apoptosis-facilitating organelles, but also the source of important bioactive peptides and that the disregulation of these MDPs is important in disease development. PUBLIC HEALTH RELEVANCE: 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 fact that the diseases of the elderly are primarily cancer, Alzheimer's disease and diabetes syndromes, all of which are related to dysfunction of the mitochondria. Opportunities for improving the health of such individuals 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 which 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, including diabetes and Alzheimer's. In our proposed project we will study a family of novel growth and survival factors called MDPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.