A Novel Immune Stimulatory Ligand in Autoimmunity-Associated Angiogenesis

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例拟议的项目将建立一个由两个独立实验室组成的新的跨学科团队的基础：由Joseph Holoshitz博士领导的UM医学院小组，长期以来一直专注于类风湿关节炎（RA）的病理生物学，以及由Henry Mosberg博士领导的UM药学院小组，药物化学专家。这两个团队将共同努力，基于一个高度创新的概念，合理设计新的治疗类风湿性关节炎的化合物，下面将简要讨论。在niams资助的R01资助下，我们最近发现了HLA-疾病关联的新机制，通过显示RA的单一最重要的遗传风险因素，HLA- drb1编码序列基序称为“共享表位”（SE），是激活Th17极化并增加实验性关节炎疾病严重程度的信号转导配体。此外，基于这些数据，我们合理设计了一种原型小抑制分子，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，在此基础上，多学科研究团队将能够设计针对hla相关疾病的新治疗药物。所要求的BIRT资金将用于测试这一想法，重点是RA。基于RA研究的成功，该计划可以以P01或多pi R01s的形式扩展到其他HLA相关疾病。具体来说，在这里提出的研究中，我们将：1。设计具有提高生物利用度的化合物类似物并破译其构象（Mosberg）；2. 测定其膜透性和口服有效性（Holoshitz）；3. 确定新化合物在体外和RA实验模型中的生物效应（Holoshitz）该项目非常符合BIRT的理念：它涉及一个来自不同科学领域和学校的新组建的跨学科团队；潜在的概念是非常新颖的；项目涉及高风险/高收益的研究追求；它将研究一种范式改变理论，并且；拟议的研究将为在广泛的hla相关疾病中开发新药奠定基础。

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.