A Novel Immune Stimulatory Ligand in Autoimmunity-Associated Angiogenesis

描述(申请人提供)：人类白细胞抗原(人类白细胞抗原)相关疾病的新治疗范例拟议中的项目将为一个新的跨学科团队奠定基础，该团队由两个独立的实验室组成：由约瑟夫·霍洛什茨医学博士领导的密歇根大学医学院小组，其长期专注于类风湿性关节炎(RA)的病理生物学；以及由药物化学专家亨利·莫斯伯格博士领导的密歇根大学药学院小组。这两个团队将共同努力，基于下面简要讨论的高度创新的概念，合理地设计治疗RA的新的治疗化合物。在母公司NIAMS资助的R01拨款下，我们最近发现了一种新的人类白细胞抗原-疾病关联机制，表明类风湿性关节炎最重要的遗传风险因素-被称为共享表位(SE)的人类白细胞抗原-DRB1编码序列基序是一种信号转导配体，它激活Th17极化并增加实验性关节炎的疾病严重程度。此外，基于这些数据，我们合理地设计了一个原型小抑制分子，在PM范围的剂量下发挥出强大的抗关节炎治疗效果。这项新合作的长期目标是为多学科研究团队能够为人类白细胞抗原相关疾病设计新的治疗药物奠定基础。BIRT申请的资金将用于测试这一想法，重点是RA。基于所提出的RA研究的成功，该程序可以以P01或多PI R01的形式扩展到其他与人类白细胞抗原相关的疾病。具体地说，在这里提出的研究中，我们将：1.设计具有更高生物利用度的化合物类似物并破译其构象(Mosberg)；2.确定它们的膜通透性和口服利用度(Holoshitz)；3.确定新化合物在体外和RA实验模型中的生物效应(Holoshitz)。该项目很好地符合BIRT的想法：它涉及一个来自不同科学领域和学校的新成立的跨学科团队；基本概念非常新颖；该项目涉及高风险/高收益的研究；它将检验一种改变范式的理论；以及；拟议的研究将为在广泛的人类白细胞抗原相关条件下开发新药奠定基础。

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.