Metabolic and Xenobiotic Control of Thyroid Hormone Metabolism

目前的建议侧重于这样一个概念，即甲状腺激素激活(T4到T3转换)通过 2型脱碘酶(D2)在燃料动态平衡和能量消耗中起着关键作用。这一概念 起源于对棕色脂肪组织(BAT)的研究，棕色脂肪组织是人类新生儿和 其他小型哺乳动物。最近，人类骨骼肌中D2活性的发现产生了 相当令人兴奋，因为脱碘是新陈代谢的一种常见机制 控制(1)。在这种背景下，我们立即对BAT D2在一种 饮食诱导肥胖抵抗的小鼠模型。在这个模型中，补充0.5%的胆汁酸 防止动物在进食高脂肪食物时变得超重或胰岛素抵抗。激烈的 合作研究通过以下途径首次认识到FXR非依赖的代谢途径 哪些胆汁酸与G蛋白偶联受体TGR5相互作用，从而刺激代谢中的D2 相关组织包括蝙蝠和人骨骼肌细胞。我们的初步研究表明，其他； GPCRs也刺激D2。这些惊人的数据表明，控制D2的代谢物的光谱，以及 这种机制在其中起作用的靶组织的范围可能比以前更广泛 想着。考虑到这一点，我们已经开始寻找新的D2调节物质，并已经 初步证据支持对异类化合物有显著的调控作用。了解如何 来自快速波动的内源分子和外源因子的代谢信号通过 D2通路是这些研究的主要目标。最终，通过了解这些新的机制， 甲状腺激素依赖的代谢控制，我们希望确定新的靶点和方法 代谢紊乱的治疗干预，包括II型糖尿病、肥胖和代谢紊乱 综合症。 演出现场(S)(组织、市、州) 马萨诸塞州波士顿布里格姆妇女医院医学部 小灵通398(09/04版)第2页表格第2页 首席调查员/项目主任(最后、第一、中间)：比安科，Antonio C. 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称时代共享用户名项目上的组织角色 安东尼奥·C·比安科·比安科123BWH Pi 达苏瓦，Wagner S.BWH博士毕业后 123BWH调查员 其他重要贡献者 命名项目中的组织角色 人类胚胎干细胞[X]否Q是 如果建议的项目涉及人类胚胎干细胞，请从下面的列表中列出特定细胞系(S)的注册号： Http://StemcellS.nih.qov/reqistrv/index.asp.根据需要使用续页。 如果此时不能引用某一特定行，请附上一条声明，说明将使用注册处的一行。。 细胞系 披露许可声明。仅适用于SBIR/STTR。请参阅SBIR/STTR说明。D是C3否 小灵通398(09/04版)第3页表格第2页-续 从头到尾连续地给下面的页面编号 应用程序。Po不使用诸如4a、4b之类的后缀。 首席调查员/项目主任(最后、第一、中间)：比安科，Antonio C. 必须在每张打印页和每张续页的顶部提供首席调查员/项目主任的姓名。 研究补助金 目录 页码 正面第1页 描述、绩效地点、关键人员、其他重要贡献者和人员 胚胎干细胞2-3 目录表 初始预算期间的明细预算(或模块预算) 整个拟议支持期间的预算(不适用于模块预算) BudgetsPertainingtoConsortium/ContractualArrangements(notapplicablewithModularBudget) 传记素描-首席调查员/项目主任(A/OF超过四页)6-8 其他传记小品(每份不得超过四页--见说明书)9-13 资源14 研究计划15-45 IntroductiontoRevisedApplication(Nottoexceed3pages；SBIR/STTRPhaseInottoexceed1page.). 补充申请简介(不超过一页) A.具体目标 B.背景和意义16-17 C.初步研究/进度报告/^_(项目A-D：不超过25页*)17-22 第一阶段进度报告(仅限SBIR/STTR第二阶段)f*SBIR/STTR第一阶段：项目A-D，以15页为限。 D.研究设计和方法22-38 E.人体研究39 保护人类受试者(如正面第4项标明“是”，则为必填项) 数据和安全监控计划(如果页面上的第4项被标记为是并且阶段I、II、 或建议进行III期临床试验) 纳入妇女和少数群体(如果页面上的第4项标记为“是”并且是临床研究，则为必填项) 目标/计划注册表(适用于新的和继续的临床研究) 包括儿童(如果主页上的第4项标记为“是”，则为必填项) F.脊椎动物39 G.文献被引39-44 H.联合体/合同安排 一、资源共享 J.支持函(如顾问)45 商业化计划(仅限SBIR/STTR第二阶段和快速通道) 核对表。46 Appendix(Fivecollatedsets.NopagenumberingnecessaryforAppendix.)检查是否 附录为 包括在内 除非特别请求，否则第一阶段SBIR/STTR不允许使用附录 接受出版的出版物和稿件数量(不超过10篇)10 其他项目(列表)： 小灵通398(09/04版)第4页表格第3页

The current proposal focuses on the concept that thyroid hormone activation (T4 to T3 conversion) via the type 2 deiodinase (D2)plays a critical role in fuel homeostasis and energy expenditure. This concept originated from studies in brown adipose tissue (BAT), the main thermogenic tissue in human newborns and other small mammals. Recently, the discovery of D2 activity in human skeletal muscle has generated considerable excitement as it has become clear that deiodination is a common mechanism for metabolic control (1). Given this background, we were immediately intrigued by fact that BAT D2 is up-regulated in a mouse model of resistance to diet-induced obesity. In this model, supplementation with 0.5% bile acids prevents animals from becoming overweight or insulin-resistant when placed on a high fat diet. Intense collaborative investigation resulted in the first recognition of an FXR-independent metabolic pathway through which bile acids interact with the G-protein coupled receptor TGR5 and thus stimulate D2 in metabolically relevant tissues including BAT and human skeletal myocytes. Our preliminary studies indicate that other ; GPCRs also stimulate D2. These striking data suggest that the spectrum of metabolites controlling D2, and the range of target tissues in which this mechanism is operant may be even more extensive than previously thought. With this in mind, we have begun to search for novel D2-regulating substances, and have preliminary evidence supporting significant regulatory effects for xenobiotic compounds. Understanding how metabolic signals from rapidly fluctuating endogenous molecules and xenobiotic factors are integrated via the D2 pathway is the major goal of these studies. Ultimately, by understanding these novel mechanisms for thyroid-hormone dependent metabolic control, we hope to identify new targets and approaches for therapeutic intervention in metabolic disorders including type II diabetes, obesity, and the metabolic syndrome. PERFORMANCE SITE(S) (organization, city, state) Department of Medicine, Brigham and Women's Hospital, Boston MA PHS 398 (Rev. 09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): BIANCO, ANTONIO C. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project BIANCO, ANTONIO C. acb123 BWH PI DA SUVA, WAGNER S. BWH POST-DOC LARSEN, P. REED pr!123 BWH INVESTIGATOR OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [X] No Q Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://StemcellS.nih.qov/reqistrv/index.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. . Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. d Yes C3 No PHS 398 (Rev. 09/04) Page 3 Form Page 2-contlnued Number the following pages consecutively throughout the application. Po not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): BIANCO, ANTONIO C. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells 2-3 Table of Contents Detailed Budget for Initial Budget Period (or Modular Budget) Budget for Entire Proposed Period of Support (not applicable with Modular Budget) BudgetsPertainingtoConsortium/ContractualArrangements(notapplicablewithModularBudget) Biographical Sketch - Principal Investigator/Program Director (A/of to exceed four pages) 6-8 Other Biographical Sketches (Not to exceed four pages for each - Seeinstructions) 9-13 Resources 14 Research Plan 15-45 IntroductiontoRevisedApplication(Nottoexceed3pages;SBIR/STTRPhaseInottoexceed1page.). Introduction to Supplemental Application (Notto exceed one page) A. Specific Aims B. Background and Significance 16-17 C. Preliminary Studies/Progress Report/ ^_ (Items A-D: not to exceed 25 pages*) 17-22 Phase I Progress Report (SBIR/STTR Phase II ONLY) f * SBIR/STTR Phase I: Items A-D limited to 15pages. D. Research Design and Methods 22-38 E. Human Subjects Research 39 Protection of Human Subjects (Required if Item 4 on the Face Page is marked "Yes") Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked "Yes" and a Phase I, II, or III clinical trial is proposed) Inclusion of Women and Minorities (Required if Item 4 on the Face Page is marked "Yes" and is Clinical Research) Targeted/Planned Enrollment Table (for new and continuing clinical research studies) Inclusion of Children (Required if Item 4 on the Face Page is marked "Yes") F. Vertebrate Animals 39 G. Literature Cited 39-44 H. Consortium/Contractual Arrangements I. Resource Sharing J. Letters of Support (e.g., Consultants) 45 Commercialization Plan (SBIR/STTR Phase II and Fast-Track ONLY) Checklist. 46 Appendix(Fivecollatedsets.NopagenumberingnecessaryforAppendix.) Checkif Appendix is Included Appendices NOT PERMITTED for Phase I SBIR/STTR unless specifically solicited Number of publications and manuscripts accepted for publication (notto exceed 10) 10 Other items (list): PHS 398 (Rev. 09/04) Page 4 Form Page 3