A Novel Immune Stimulatory Ligand in Autoimmunity-Associated Angiogenesis

自身免疫相关血管生成中的新型免疫刺激配体

• 批准号: 8581467
• 负责人: Joseph Holoshitz
• 金额: $ 15.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581467
• 关键词: Affinity; Amino Acid Substitution; Animal Experiments; Arthritis; Autoimmune Process; Autoimmunity; Biological Assay; Biological Availability; Caco-2 Cells; Cell Membrane Permeability; Code; Collaborations; Collagen Arthritis; Computing Methodologies; Cyclic Peptides; Cyclization; Data; Development; Disease; Disease Association; Doctor of Philosophy; Dose; Drug Kinetics; Epitopes; Experimental Arthritis; Experimental Models; Foundations; Funding; Future; Goals; Grant; HLA Antigens; Head; Immune; In Vitro; Inflammatory; Laboratories; Lead; Ligands; Molecular Conformation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oral; Osteoclasts; Parents; Pathway interactions; Pemphigus Vulgaris; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacy facility; Research; Research Personnel; Rheumatoid Arthritis; Schools; Severity of illness; Signal Transduction; Solutions; System; Testing; Therapeutic Agents; Therapeutic Effect; Vertebral column; analog; angiogenesis; base; bone; calreticulin; chromophore; college; design; genetic risk factor; high risk; improved; in vivo; innovation; insight; medical schools; multidisciplinary; novel; novel therapeutics; programs; public health relevance; receptor; success; theories

DESCRIPTION (provided by applicant): A New Treatment Paradigm for Human Leukocyte Antigen (HLA)-Associated Diseases The proposed project will build the foundation of a new interdisciplinary team consisting of 2 independent laboratories: a UM Medical School group headed by Joseph Holoshitz, MD, whose longstanding focus has been on the pathobiology of rheumatoid arthritis (RA), and a group at the UM College of Pharmacy, headed by Henry Mosberg, PhD, an expert in medicinal chemistry. The 2 teams will join efforts to rationally design new therapeutic compounds for RA, based on a highly innovative concept, discussed briefly below. Under the parent NIAMS-funded R01 grant, we have recently uncovered a novel mechanism of HLA- disease association, by showing that the single most important genetic risk factor for RA, a HLA-DRB1- coded sequence motif called 'shared epitope' (SE), is a signal transduction ligand that activates Th17 polarization and increases disease severity in experimental arthritis. Moreover, based on these data, we have rationally designed a prototypic small inhibitory molecule that exerts potent anti-arthritis therapeutic effects at pM-range doses. The long-term goal of the new collaboration is to establish the foundations on which multidisciplinary teams of investigators will be able to design new therapeutic agents for HLA-associated diseases. The requested BIRT funds will be used to test-pilot the idea, focusing on RA. Based on the success of the proposed studies in RA, the program could be extended in the format of P01, or multi-PI R01s, to other HLA- associated conditions. Specifically, in the studies proposed here, we will: 1. Design compound analogs with improved bioavailability and decipher their conformation (Mosberg); 2. Determine their membrane permeability and oral availability (Holoshitz); 3. Determine the biologic effects of the new compounds both in vitro and in an experimental model of RA (Holoshitz). The project conforms well with the BIRT idea: It involves a newly formed interdisciplinary team from distinct scientific fields and schools; the underlying concept is highly novel; the project involves a high-risk/high yield research pursuit; it will examine a paradigm-changing theory, and; the proposed studies will build the foundations on which novel drugs could be developed in a wide-range of HLA-associated conditions.

描述（由申请人提供）：人类白细胞抗原（HLA）相关疾病的新治疗范式将建立一个新的跨学科团队的基础，该团队由2个独立实验室组成：由Joseph Holoshitz领导的UM医学院小组。由亨利·莫斯伯格（Henry Mosberg）博士领导，是药物化学专家。这两个团队将基于一个高度创新的概念，为RA合理设计新的治疗化合物的努力，在下面简要讨论。在父母NIAMS资助的R01赠款的下，我们最近发现了HLA-DISEAS协会的一种新型机制，它表明RA的单个最重要的遗传危险因素是HLA-DRB1编码序列图案，称为“共享表位”（SE），是一种信号转移率，可激活TH17极性化和增加实验性的疾病性疾病性疾病性疾病，并增加了TH17极性疾病的严重性。此外，根据这些数据，我们合理地设计了一种原型的小抑制分子，该分子在PM范围内发挥有效的抗关节炎治疗作用。新合作的长期目标是建立基础，跨学科团队的研究人员将能够为HLA相关疾病设计新的治疗剂。请求的BIRT资金将用于测试巡回演出，重点是RA。根据RA中提出的研究的成功，该程序可以以P01或Multi-Pi R01的格式扩展到其他与HLA相关的条件。具体而言，在此处提出的研究中，我们将：1。设计化合物类似物，具有改善的生物利用度并破译其构象（Mosberg）； 2。确定它们的膜渗透性和口服可用性（Holoshitz）； 3。在体外和RA的实验模型（Holoshitz）中确定新化合物的生物学效应。该项目符合Birt的想法：它涉及来自不同科学领域和学校的新成立的跨学科团队；基础概念是高度新颖的。该项目涉及高风险/高收益研究追求；它将研究一种改变范式的理论，并；拟议的研究将建立在与HLA相关的大量相关条件下可以开发新药物的基础。