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公开(公告)号：US20100105036A1
公开(公告)日：2010-04-29
申请号：US12408575
申请日：2009-03-20
CPC分类号： C12Q1/68 , C12Q1/44 , G01N2333/4703 , G01N2333/916 , G01N2500/02
摘要： This invention relates to methods of screening compounds that modulate cellular and organismal processes by modification of the activity of SIR2 and/or transcription factors, e.g., p53, particularly methods of screening for compounds that modify lifespan and/or metabolism of a cell or an organism by modulation of the activity of SIR2 and/or transcription factors, e.g., p53, and more particularly to methods of screening for compounds that modulate the activity of Sir2 and/or transcription factors, e.g., p53. In particular, the present invention relates to a method for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound. The invention further relates to therapeutic uses of said compounds. The invention further relates to a method of modifying the acetylation status of a transcription factor binding site on histone or DNA by raising local concentrations of Sir2.
摘要翻译： 本发明涉及通过修饰SIR2和/或转录因子活性（例如p53）来筛选调节细胞和生物体过程的化合物的方法，特别是筛选修饰细胞或生物体的寿命和/或代谢的化合物的方法 通过调节SIR2和/或转录因子例如p53的活性，更具体地涉及筛选调节Sir2和/或转录因子例如p53的活性的化合物的方法。 特别地，本发明涉及通过提供包含转录因子Sir2和Sir2辅因子与该化合物的测试混合物来筛选化合物的方法，并且在存在下评价测试混合物的组分的活性 化合物。 本发明还涉及所述化合物的治疗用途。 本发明还涉及通过提高Sir2的局部浓度来改变组蛋白或DNA上的转录因子结合位点的乙酰化状态的方法。
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公开(公告)号：US20060252076A1
公开(公告)日：2006-11-09
申请号：US11404146
申请日：2006-04-13
CPC分类号： C12Q1/68 , C12Q1/44 , G01N2333/4703 , G01N2333/916 , G01N2500/02
摘要： This invention relates to methods of screening compounds that modulate cellular and organismal processes by modification of the activity of SIR2 and/or transcription factors, e.g., p53, particularly methods of screening for compounds that modify lifespan and/or metabolism of a cell or an organism by modulation of the activity of SIR2 and/or transcription factors, e.g., p53, and more particularly to methods of screening for compounds that modulate the activity of Sir2 and/or transcription factors, e.g., p53. In particular, the present invention relates to a method for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound. The invention further relates to therapeutic uses of said compounds. The invention further relates to a method of modifying the acetylation status of a transcription factor binding site on histone or DNA by raising local concentrations of Sir2.
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公开(公告)号：US20130071378A1
公开(公告)日：2013-03-21
申请号：US13523412
申请日：2012-06-14
IPC分类号： C12Q1/68
CPC分类号： C12Q1/68 , C12Q1/44 , G01N2333/4703 , G01N2333/916 , G01N2500/02
摘要： Methods for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound are described.
摘要翻译： 描述了通过向化合物提供包含转录因子Sir2和Sir2辅因子的测试混合物并在化合物存在下评价测试混合物的组分的活性来筛选化合物的方法。
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公开(公告)号：US07572575B2
公开(公告)日：2009-08-11
申请号：US11404146
申请日：2006-04-13
IPC分类号： C12Q1/00 , G01N33/53 , G01N33/567
CPC分类号： C12Q1/68 , C12Q1/44 , G01N2333/4703 , G01N2333/916 , G01N2500/02
摘要： This invention relates to methods of screening compounds that modulate cellular and organismal processes by modification of the activity of SIR2 and/or transcription factors, e.g., p53, particularly methods of screening for compounds that modify lifespan and/or metabolism of a cell or an organism by modulation of the activity of SIR2 and/or transcription factors, e.g., p53, and more particularly to methods of screening for compounds that modulate the activity of Sir2 and/or transcription factors, e.g., p53. In particular, the present invention relates to a method for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound. The invention further relates to therapeutic uses of said compounds. The invention further relates to a method of modifying the acetylation status of a transcription factor binding site on histone or DNA by raising local concentrations of Sir2.
摘要翻译： 本发明涉及通过修饰SIR2和/或转录因子（例如p53）的活性来调节细胞和生物体过程的化合物的方法，特别是筛选修饰细胞或生物体的寿命和/或代谢的化合物的方法 通过调节SIR2和/或转录因子例如p53的活性，更具体地涉及筛选调节Sir2和/或转录因子例如p53的活性的化合物的方法。 特别地，本发明涉及通过提供包含转录因子Sir2和Sir2辅因子与该化合物的测试混合物来筛选化合物的方法，并且在存在下评价测试混合物的组分的活性 化合物。 本发明还涉及所述化合物的治疗用途。 本发明还涉及通过提高Sir2的局部浓度来改变组蛋白或DNA上的转录因子结合位点的乙酰化状态的方法。
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5.发明授权公开(公告)号：US07452664B2
公开(公告)日：2008-11-18
申请号：US09461580
申请日：1999-12-15
CPC分类号： G01N33/66 , A61K38/1709 , C12Q1/48 , G01N2500/00 , Y02A50/473 , A61K2300/00
摘要： Methods of identifying agents which alter the NAD-dependent acetylation status and mono-ADP-ribosylation of nuclear proteins are disclosed. The methods further include identifying agents which alter the life span or aging of a cell or an organism by determining the level of NAD-dependent acetylation and/or ADP ribosylation of a nuclear protein. The invention also relates to a mammalian Sir2 protein which acetylates or deacetylates nuclear proteins in a NAD-dependent manner and has mono-ADP-ribosyltransferase activity. Host cells producing the Sir2 protein and antibodies to the Sir2 protein are also provided.
摘要翻译： 公开了鉴定改变核蛋白的NAD依赖性乙酰化状态和单ADP-核糖基化的试剂的方法。 所述方法还包括通过确定核蛋白的NAD依赖性乙酰化和/或ADP核糖基化的水平来鉴定改变细胞或生物体的寿命或衰老的试剂。 本发明还涉及哺乳动物Sir2蛋白，其以NAD依赖性方式乙酰化或脱乙酰化核蛋白并具有单ADP-核糖基转移酶活性。 还提供了产生Sir2蛋白的宿主细胞和Sir2蛋白的抗体。
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6.发明授权Methods for identifying agents that alter NAD-dependent deacetylation activity of a SIR2 protein 有权用于鉴定改变SIR2蛋白的NAD依赖性脱乙酰活性的试剂的方法公开(公告)号：US08642284B1
公开(公告)日：2014-02-04
申请号：US09735786
申请日：2000-12-13
CPC分类号： C12Q1/48 , G01N2333/98 , G01N2440/10 , G01N2500/00
摘要： Methods of identifying agents which alter the NAD-dependent deacetylation activity of a Sir2 protein or a fragment of a Sir2 protein are disclosed. The acetylated protein can be a nuclear protein, such as a histone protein, or a cytoplasmic protein. The Sir2 protein employed in the methods can include at least a core domain of a Sir2 protein, such as a human Sir2 protein.
摘要翻译： 公开了鉴定改变Sir2蛋白或Sir2蛋白片段的NAD依赖性脱乙酰活性的试剂的方法。 乙酰化蛋白可以是核蛋白，例如组蛋白，或细胞质蛋白。 用于该方法的Sir2蛋白质可以包括Sir2蛋白质的至少核心结构域，例如人Sir2蛋白质。
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7.发明授权公开(公告)号：US08652797B2
公开(公告)日：2014-02-18
申请号：US12209847
申请日：2008-09-12
CPC分类号： G01N33/66 , A61K38/1709 , C12Q1/48 , G01N2500/00 , Y02A50/473 , A61K2300/00
摘要： Methods of NAD-dependent of at least one lysine residue in an acetylated protein are disclosed. The methods include combining the acetylated protein with an isolated Sir2 protein or fragment that includes a core domain of the Sir2 protein. The Sir2 protein or fragment of the Sir2 protein can include a human Sir2 protein or a fragment of a human Sir2 protein.
摘要翻译： 公开了乙酰化蛋白中至少一个赖氨酸残基的NAD依赖性的方法。 所述方法包括将乙酰化蛋白与包含Sir2蛋白的核心结构域的分离的Sir2蛋白或片段组合。 Sir2蛋白或Sir2蛋白的片段可以包括人Sir2蛋白或人Sir2蛋白的片段。
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公开(公告)号：US20070099830A1
公开(公告)日：2007-05-03
申请号：US11409170
申请日：2006-04-21
申请人： Leonard Guarente , Marcia Haigis
发明人： Leonard Guarente , Marcia Haigis
CPC分类号： C12N15/1137 , C12N9/80 , C12Q1/48 , G01N2333/91142
摘要： It has been discovered that Sirt4 possesses an ADP-ribosyltransferase activity. Sirt4 is localized to mitochondria, where it binds to and regulates the activity of proteins such as glutamate dehydrogenase. The ADP-ribosyltransferase activity of Sirt4 is important for the regulation of biological functions such as insulin secretion. Methods of screening for compounds that modulate the expression or activity of Sirt4 are provided. Also provided are methods of modulating insulin secretion, treating metabolic disorders, and treating neurodegenerative disorders by modulating the expression or activity of Sirt4.
摘要翻译： 已经发现Sirt4具有ADP-核糖基转移酶活性。 Sirt4被定位于线粒体，其中它结合并调节蛋白质如谷氨酸脱氢酶的活性。 Sirt4的ADP-核糖基转移酶活性对调节生物学功能如胰岛素分泌是重要的。 提供筛选调节Sirt4表达或活性的化合物的方法。 还提供了调节胰岛素分泌，治疗代谢紊乱和通过调节Sirt4的表达或活性来治疗神经变性疾病的方法。
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公开(公告)号：US20050164969A1
公开(公告)日：2005-07-28
申请号：US10993903
申请日：2004-11-19
申请人： Gil Blander , Leonard Guarente
发明人： Gil Blander , Leonard Guarente
CPC分类号： C12N9/18 , C07K14/4746
摘要： The present invention provides new and advantageous methods, compositions, cell constructs and animal models related to inhibiting the senescence of vertebrate cells and vertebrate organisms based on the use of SIRT1 polynucleotides and polypeptides, as well as mutant SIRT1 polynucleotides and polypeptides. The invention provides polynucleotides that encode variants and fragments of SIRT1 polypeptides, and also provides variant SIRT1 polypeptides and fragments thereof. Additionally the invention provides a method of inhibiting or delaying the expression in a vertebrate cell of a protein having biological activity associated with loss of population doubling in the cell. The invention further provides a method of treating a pathology, a disease or a medical condition in a subject, wherein the pathology responds to an SIRT1 polypeptide. The invention also provides a vertebrate cell that incorporates a heterologous nucleic acid encoding a variant of SIRT1, or a fragment thereof, as well as a transgenic mammal a majority of whose cells harbor a transgene including a nucleic acid sequence encoding an SIRT1 polypeptide. The invention also provides an antibody that binds immunospecifically to a variant SIRT1 polypeptide or a fragment thereof, and a method of determining whether the amount of an SIRT1 polypeptide in a sample differs from the amount of the SIRT1 polypeptide in a reference. The invention further provides a method of contributing to the diagnosis or prognosis of, or to developing a therapeutic strategy for, a disease or pathology in a subject, wherein the disease or pathology responds to treatment with an SIRT1 polypeptide and wherein the amount of SIRT1 polypeptide in the pathology is known to differ from the amount of the SIRT1 polypeptide in a nonpathological state.
摘要翻译： 本发明提供了基于使用SIRT1多核苷酸和多肽以及突变型SIRT1多核苷酸和多肽来抑制脊椎动物细胞和脊椎动物生物衰老有关的新的和有利的方法，组合物，细胞构建体和动物模型。 本发明提供编码SIRT1多肽的变体和片段的多核苷酸，并且还提供变体SIRT1多肽及其片段。 另外，本发明提供了抑制或延迟具有生物活性的蛋白质的脊椎动物细胞中表达的方法，所述生物活性与细胞中群体倍增的丧失相关。 本发明还提供了治疗受试者的病理学，疾病或医学病症的方法，其中所述病理学响应于SIRT1多肽。 本发明还提供了一种脊椎动物细胞，其包含编码SIRT1的变体或其片段的异源核酸，以及转基因哺乳动物，其大部分细胞含有包含编码SIRT1多肽的核酸序列的转基因。 本发明还提供了与变体SIRT1多肽或其片段免疫特异性结合的抗体，以及确定样品中SIRT1多肽的量是否与参考文献中SIRT1多肽的量不同的方法。 本发明进一步提供了一种有助于对受试者的疾病或病理学的诊断或预后或制定治疗策略的方法，其中所述疾病或病理学响应于SIRT1多肽的治疗，并且其中SIRT1多肽的量 在病理学中已知与非病理状态下SIRT1多肽的量不同。
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公开(公告)号：US20100240029A1
公开(公告)日：2010-09-23
申请号：US12303721
申请日：2007-06-06
申请人： Leonard Guarente , Monty Krieger , Xiaoling Li
发明人： Leonard Guarente , Monty Krieger , Xiaoling Li
IPC分类号： C12Q1/68 , C07K14/435 , G01N33/68 , C07J9/00 , C07C59/00 , C12N15/00 , G01N33/559
CPC分类号： G01N33/92 , G01N33/6872 , G01N2500/02 , G01N2800/044 , G01N2800/323
摘要： A cholesterol-regulating complex of SIRT1 and LXR and methods of use are disclosed. SIRT1 forms a complex with LXR bound to an LXR element. Methods of forming the complex, identifying an agent that modulates formation of the complex, increasing the ratio of cholesterol bound to high density lipoprotein (HDL) to total cholesterol in the plasma of a mammal, promoting ABCA1-mediated cholesterol efflux from a mammalian cell, treating a subject deemed to have a level of SIRT1 activity that is below normal, assessing whether a candidate substance modulates an LXR-dependent process, and assessing whether a candidate substance modulates an SIRT1-dependent effect of an LXR are disclosed.
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