公开(公告)号：WO2011130729A3

公开(公告)日：2012-03-29

申请号：PCT/US2011032848

申请日：2011-04-18

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  JONKER JOHAN W ,  DOWNES MICHAEL ,  EVANS ROLAND M ,  SUH JAEMYOUNG

Inventor： JONKER JOHAN W ,  DOWNES MICHAEL ,  EVANS RONALD M ,  SUH JAEMYOUNG

IPC: A61K38/18 ,  A61P3/00 ,  A61P3/04 ,  A61P3/10

CPC classification number: A61K38/1825 ,  A61K9/0019 ,  A61K31/4439 ,  A61K45/06 ,  A61K47/60 ,  A61K47/61 ,  A61K2300/00

Abstract: The method provides methods and compositions for treating metabolic disorders such as impaired glucose tolerance, elevated blood glucose, insulin resistance, dyslipidaemia, obesity, and fatty liver.

Abstract translation: 该方法提供了用于治疗代谢紊乱的方法和组合物，例如葡萄糖耐量降低，血糖升高，胰岛素抵抗，血脂异常，肥胖症和脂肪肝。

公开(公告)号：WO2011032025A2

公开(公告)日：2011-03-17

申请号：PCT/US2010048507

申请日：2010-09-10

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  SUGII SHIGEKI ,  EVANS ROLAND M ,  BELMONTE JUAN CARLOS IZPISUA ,  KIDA YASUYUKI

Inventor： SUGII SHIGEKI ,  EVANS RONALD M ,  BELMONTE JUAN CARLOS IZPISUA ,  KIDA YASUYUKI

IPC: C12N5/0775 ,  C12N5/02 ,  C12N5/10 ,  C12N15/12

CPC classification number: C12N5/0696 ,  C12N2500/90 ,  C12N2500/98 ,  C12N2501/602 ,  C12N2501/603 ,  C12N2501/604 ,  C12N2501/606 ,  C12N2506/1384 ,  C12N2510/00

Abstract: Methods and compositions for generating adipose-derived induced pluripotent stem cells for humans and animals and their use are provided.

Abstract translation: 提供用于产生用于人和动物的脂肪来源的诱导性多能干细胞的方法和组合物及其用途。

公开(公告)号：WO2009086526A3

公开(公告)日：2009-09-03

申请号：PCT/US2008088466

申请日：2008-12-29

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  EVANS ROLAND M ,  NARKAR VIHANG A ,  SHAW REUBEN J ,  DOWNES MICHAEL ,  YU RUTH T

Inventor： EVANS RONALD M ,  NARKAR VIHANG A ,  SHAW REUBEN J ,  DOWNES MICHAEL ,  YU RUTH T

IPC: A61K31/70

CPC classification number: A61K31/47

Abstract: Agonists of AMP-activated protein kinase (AMPK) improve exercise and modify energy metabolism in a subject A combination of AMPK and peroxisome proliferator-activated receptor (PPAR) delta agonists may also be used to improve exercise performance in a subject Methods for identifying substance-enhanced exercise performance in a subject, and methods for identifying compounds that affect the interaction of PPAR6 with exercise-induced kinases are also disclosed.

Abstract translation: AMP激活蛋白激酶（AMPK）的激动剂改善受试者的运动和改变能量代谢AMPK和过氧化物酶体增殖物激活受体（PPAR）δ激动剂的组合也可用于改善受试者的运动性能。 增强受试者的运动表现，以及用于鉴定影响PPAR6与运动诱导的激酶相互作用的化合物的方法。

公开(公告)号：WO2012058634A3

公开(公告)日：2012-07-12

申请号：PCT/US2011058454

申请日：2011-10-28

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  EVANS ROLAND M ,  ECKER JOSEPH R ,  LISTER RYAN

Inventor： EVANS RONALD M ,  ECKER JOSEPH R ,  LISTER RYAN

IPC: C12N5/0735 ,  C12N5/10 ,  C12N15/85 ,  C12Q1/02

CPC classification number: C12Q1/6881 ,  C12N2799/027 ,  C12Q2600/154

Abstract: Provided herein are methods of characterizing the epigenetic signature of human induced pluripotent stem cells. The methods are useful in identifying human induced pluripotent stem cells (hiPSCs), diagnostic markers for incomplete hiPSCs reprogramming, and characterization of the efficacy of different reprogramming techniques.

Abstract translation: 本文提供了表征人诱导性多能干细胞的表观遗传学标记的方法。 该方法可用于鉴定人诱导的多能干细胞（hiPSC），用于不完全hiPSC重编程的诊断标记，以及不同重编程技术的功效表征。

公开(公告)号：WO2010025420A3

公开(公告)日：2010-07-01

申请号：PCT/US2009055441

申请日：2009-08-28

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  JONKER JOHAN W ,  DOWNES MICHAEL ,  EVANS ROLAND M

Inventor： JONKER JOHAN W ,  DOWNES MICHAEL ,  EVANS RONALD M

IPC: C12Q1/68 ,  C12N5/10 ,  C12N15/09

CPC classification number: C12Q1/6897 ,  C12N15/1086

Abstract: Provided herein is, inter alia, methods and compositions useful in therapeutic interrogation of complex physiologic pathways by massively parallel and permissive transcriptional screening. Thus, methods and compositions are provided herein that are useful for high-throughput functional analysis of complex, transcriptionally regulated physiological pathways. While examples are provided relating to nuclear receptors, the methods and composition can be generalized and applied to any class of transcription factor or any class of gene product that can regulate the activity of transcription. For example, in addition to nuclear receptors, the methods and compositions provided herein are generally applicable to all known transcription factors and any gene encoded product that modulates said transcription factor activity. Moreover, data obtained through the methods provided herein are directly comparable thereby facilitating high-throughput functional analysis.

Abstract translation: 本文提供的方法和组合物尤其适用于通过大规模平行且允许的转录筛选对复杂生理途径进行治疗性询问。 因此，本文提供了用于复杂的，转录调节的生理途径的高通量功能分析的方法和组合物。 虽然提供了与核受体相关的实例，但是该方法和组合物可以推广并应用于任何类别的转录因子或可以调节转录活性的任何类别的基因产物。 例如，除核受体之外，本文提供的方法和组合物通常适用于所有已知的转录因子和调节所述转录因子活性的任何基因编码产物。 此外，通过本文提供的方法获得的数据可直接比较，从而有利于高通量功能分析。

公开(公告)号：WO2004046323A3

公开(公告)日：2004-12-09

申请号：PCT/US0336548

申请日：2003-11-14

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  DOWNES MICHAEL R ,  VERDICIA MARK A ,  NOEL JOSEPH P ,  EVANS ROLAND M ,  BOWMAN LINDSEY J ,  BOWMAN MARIANNE

Inventor： DOWNES MICHAEL R ,  VERDICIA MARK A ,  NOEL JOSEPH P ,  EVANS RONALD M ,  BOWMAN LINDSEY J ,  BOWMAN MARIANNE

IPC: C07K14/705 ,  G06F19/00 ,  G06F19/16 ,  C08H1/00

CPC classification number: C07K14/70567 ,  C07K2299/00 ,  G01N33/743 ,  G01N2500/00 ,  G06F19/16 ,  G06F19/706

Abstract: The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist, fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a three-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.

Abstract translation: 本发明提供了包含结晶形式的法尼醇X受体（FXR）的配体结合结构域（LBD）的组合物。 在可选的实施方案中，FXR的LBD与其配体络合。 提供了与新型高亲和力激动剂fexaramine复合的FXR的高分辨率结构。 所发现的FXR LBD结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明进一步提供用于产生FXR或其复合物的三维表示的计算机，以及用于确定FXR或其复合物的至少一部分结构坐标的计算机。 本发明还提供了使用这种结构信息预测能够结合FXR的分子的方法; 鉴定具有FXR的激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明进一步提供了包含由这种发明方法鉴定的化合物的组合物

公开(公告)号：WO9601317A3

公开(公告)日：1996-04-18

申请号：PCT/US9508193

申请日：1995-06-27

Applicant: SALK INST FOR BIOLOGICAL STUDI

Inventor： EVANS RONALD M ,  FOREMAN BARRY M ,  KLIEWER STEVEN A ,  ONG ESTELITA S

IPC: C12N15/09 ,  C07K14/705 ,  C07K16/28 ,  C12N5/10 ,  C12N15/12 ,  C12P21/08 ,  C12Q1/68 ,  G01N33/74 ,  C12N15/85 ,  C12Q1/00

CPC classification number: C07K14/705 ,  C07K14/70567 ,  G01N33/74 ,  G01N2500/00

Abstract: Peroxisome proliferator-activated receptor subunits designated PPARη and PPARδ are described. Nucleic acid sequences encoding the receptor subunits, expression vectors containing such sequences and host cells transformed with such vectors are also disclosed, as are heterodimeric PPAR receptors comprising at least one of the invention subunits, and methods for the expression of such novel receptors, and various uses therefor.

公开(公告)号：WO2016172153A3

公开(公告)日：2017-01-12

申请号：PCT/US2016028365

申请日：2016-04-20

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  FLORIDA STATE UNIV RES FOUND INCORPORATED

Inventor： EVANS RONALD M ,  DOWNES MICHAEL ,  ATKINS ANNETTE ,  YU RUTH T ,  BLABER MICHAEL ,  XIA XUE

IPC: A61K38/18 ,  C07K14/50

CPC classification number: C07K14/503 ,  A61K38/00 ,  A61K38/1825 ,  A61K38/28 ,  A61K45/06 ,  A61K47/6425 ,  A61K48/00 ,  C07K14/50 ,  C07K14/501 ,  C07K14/705 ,  C07K2319/00 ,  C07K2319/70 ,  C07K2319/75 ,  C12N15/00 ,  C12N2015/8518 ,  C12Q1/54 ,  A61K2300/00

Abstract: The present disclosure provides FGF1 mutant proteins having one or more mutations in the heparin binding domain. Such mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.

Abstract translation: 本公开提供了在肝素结合结构域中具有一个或多个突变的FGF1突变蛋白。 这样的突变体也可以具有N-末端缺失，点突变或其组合。 在一些实例中，突变FGF1蛋白具有降低的促有丝分裂活性。 还提供了编码这些蛋白质的核酸分子，以及包括这种核酸的载体和细胞。 所公开的FGF1突变体可以降低哺乳动物的血糖，并且在一些实例中用于治疗代谢紊乱。

公开(公告)号：WO2016100820A3

公开(公告)日：2016-11-03

申请号：PCT/US2015066683

申请日：2015-12-18

Applicant: SALK INST FOR BIOLOGICAL STUDI

Inventor： EVANS RONALD M ,  DOWNES MICHAEL ,  ATKINS ANNETTE ,  SUH JAE MYOUNG ,  YU RUTH T

IPC: A61K38/18 ,  C07K14/50 ,  C07K19/00

CPC classification number: C07K14/503 ,  A61K38/1825

Abstract: The present disclosure provides FGF2 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Thus, the disclosed mutant FGF2 proteins can be used to treat one or more metabolic diseases. In some examples, mutant FGF2 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels, for example to treat a metabolic disorder are also provided.

Abstract translation: 本公开提供了FGF2突变蛋白，例如具有N端缺失，点突变或其组合的FGF2突变蛋白，其可以降低哺乳动物的血糖。 因此，所公开的突变FGF2蛋白可以用于治疗一种或多种代谢疾病。 在一些例子中，突变FGF2蛋白具有降低的促有丝分裂活性。 还提供了编码这种蛋白质的核酸分子，以及包含这种核酸的载体和细胞。 还提供了使用公开的分子降低血糖水平的方法，例如用于治疗代谢病症。

公开(公告)号：WO2004046068A2

公开(公告)日：2004-06-03

申请号：PCT/US0336137

申请日：2003-11-14

Applicant: SALK INST FOR BIOLOGICAL STUDI ,  DOWNES MICHAEL R ,  EVANS ROLAND M

Inventor： DOWNES MICHAEL R ,  EVANS RONALD M

IPC: A61K20060101 ,  A61K31/16 ,  A61K31/21 ,  A61K31/215 ,  A61K31/33 ,  A61K31/35 ,  A61K31/353 ,  C07C20060101 ,  C07D311/04 ,  C07D311/74 ,  C07C

CPC classification number: C07D311/94 ,  A61K31/16 ,  A61K31/353 ,  A61K31/44 ,  A61K31/4433 ,  C07C233/54 ,  C07C233/63 ,  C07C233/81 ,  C07C237/22 ,  C07C275/42 ,  C07C309/66 ,  C07C323/40 ,  C07C2601/02 ,  C07C2601/04 ,  C07C2601/08 ,  C07C2601/14 ,  C07D213/40 ,  C07D277/28 ,  C07D307/46 ,  C07D311/04 ,  C07D311/22 ,  C07D311/64 ,  C07D311/68 ,  C07D317/58 ,  C07D333/20 ,  C07D333/22 ,  C07D407/12 ,  C07D409/12

Abstract: The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.

Abstract translation: 对胆固醇合成，代谢，获取和运输的有效调节是脂质体内平衡的重要组成部分。 法尼醇X受体（FXR）是胆汁酸的转录传感器，胆固醇代谢的主要产物。 因此，开发FXR的有效的，选择性的小分子激动剂，部分激动剂和拮抗剂将是进一步解卷积FXR生理学的重要步骤。 根据本发明，描述了新的有效FXR活化剂的鉴定。 带有芪或联芳基部分的本发明化合物的两种衍生物包含迄今为止在基于细胞的测定中报道的最有效的FXR激动剂的成员。 这些化合物可用作化学工具以进一步确定FXR的生理学作用以及治疗与胆固醇，胆汁酸及其代谢和动态平衡有关的疾病的治疗导向。