Targeting Multiple Diseases Through Gamma Secretase

通过伽玛分泌酶针对多种疾病

• 批准号: 8415150
• 负责人: BARBARA A OSBORNE
• 金额: $ 98.08万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415150
• 关键词: Address; Aging; Alzheimer' s Disease; Amyloid Proteins; Antineoplastic Agents; Biochemical; Biochemistry; Biological; Biological Assay; Biological Markers; Breast Cancer Treatment; Catalytic Domain; Cell Nucleus; Cells; Chemistry; Cleaved cell; Clinic; Collaborations; Communities; Complex; Complication; Coupled; Cytoplasmic Tail; Data; Development; Disease; ERBB2 gene; Environment; Enzymes; Estrogen Receptors; Event; Generations; Goals; Growth; Health; Hematopoietic stem cells; Human; Human Resources; In Vitro; Instruction; Integral Membrane Protein; Investigation; Lead; Lipid Bilayers; Malignant Neoplasms; Mediating; Membrane; Mus; Outcome; Peptide Hydrolases; Principal Investigator; Property; Protein Fragment; Proteins; Proteolysis; Publishing; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Transmembrane Domain; Work; base; data sharing; design; gamma secretase; graft vs host disease; host neoplasm interaction; human disease; in vivo; inhibitor/antagonist; insight; leukemia; malignant breast neoplasm; member; nicastrin protein; notch protein; novel; overexpression; presenilin-1; presenilin-2; progesterone receptor negative; programs; research study; secretase; therapeutic target; triple-negative invasive breast carcinoma; tumor growth

DESCRIPTION (provided by applicant): This Program proposes an overarching hypothesis that rational targeting of ?-secretase, a multi-subunit intramembrane cleaving protease that has several biologically important substrates, may be considered as a therapeutic target for a number of diseases. The three projects in this Program address the use of ?-secretase inhibitors in breast cancer (Project 1), and graft-versus-host disease (Project 2), and propose biochemical strategies to enable us to better understand the mechanism of action of ?-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of ?-secretase inhibition in normal, as well as, disease settings. The Principal Investigators of this Program have worked together, shared data and published as a group for the past six years. The Program is significantly enhanced by a Chemistry Core that has the proven ability to synthesize a wide variety of ?-secretase inhibitors that allow members of the Program to explore the biological properties of these inhibitors in an environment free from commercial restriction. Such an approach will provide a scientific basis for optimal GSI selection matched to a particular disease.

描述（由申请人提供）：该程序提出了一个总体假设：secretase的合理靶向是一种具有多种生物学上重要底物的多支化膜内切割蛋白酶，可以视为多种疾病的治疗靶标。该计划中的三个项目涉及 - 分泌酶抑制剂在乳腺癌中的使用（项目1）和移植物与宿主疾病（项目2），并提出了生化策略，以使我们能够更好地理解？ - 泌尿药酶的作用机制（项目3）。这些项目的整合，以更好地理解正常和疾病环境中分泌酶抑制的作用机理。该计划的主要研究人员在过去六年中共同合作，共享数据并作为小组出版。该程序通过化学核心显着增强，该化学核心具有合成各种各样的？ - 分泌酶抑制剂的能力，该抑制剂允许该计划的成员在不含商业限制的环境中探索这些抑制剂的生物学特性。这种方法将为与特定疾病相匹配的最佳GSI选择提供科学基础。