Targeting Multiple Diseases Through Gamma Secretase

通过伽玛分泌酶针对多种疾病

基本信息

批准号：
8738618
负责人：
BARBARA A OSBORNE
金额：
$ 92.28万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
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/8738618
关键词：
Address Aging Alzheimer&apos 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

项目摘要

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）：该计划提出了一个总体假设，即β-分泌酶（一种具有多种重要生物学底物的多亚基膜内裂解蛋白酶）的合理靶向可被视为许多疾病的治疗靶点。该计划中的三个项目解决了β-分泌酶抑制剂在乳腺癌（项目1）和移植物抗宿主病（项目2）中的使用，并提出了生化策略，使我们能够更好地了解β-分泌酶抑制剂的作用机制。 -分泌酶（项目3）。这些项目的目标是更好地了解 β-分泌酶抑制在正常和疾病环境中的作用机制。在过去的六年里，该项目的主要研究人员共同努力、共享数据并作为一个小组发表论文。该计划通过化学核心得到了显着增强，该核心已被证明能够合成多种 β-分泌酶抑制剂，使该计划的成员能够在不受商业限制的环境中探索这些抑制剂的生物特性。这种方法将为与特定疾病相匹配的最佳 GSI 选择提供科学依据。