Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis

作为巨核细胞生成和血小板生成调节剂的合成糖胺聚糖模拟物

• 批准号: 10351027
• 负责人: Daniel Kwame Afosah
• 金额: $ 17.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351027
• 关键词: Advanced Development; Advisory Committees; Affinity; Binding; Binding Proteins; Biological; Biological Assay; Biology; Biopolymers; Blood; Blood Circulation; Blood Platelets; Bone Marrow; Career Choice; Charge; Chemicals; Coagulation Process; Complex; Coupled; Crystallography; Data; Development; Development Plans; Dimerization; Disease; Drug Targeting; Ensure; Environment; Excision; Extracellular Matrix; Flavonoids; Foundations; Funding; GAG Gene; Generations; Glycosaminoglycans; Hematopoietic stem cells; Heparitin Sulfate; Human; ITIM; In Vitro; Inflammation; Length; Letters; Libraries; Malignant Neoplasms; Megakaryocytes; Megakaryocytopoieses; Mentors; Mentorship; Mission; Molecular; Mus; National Heart, Lung, and Blood Institute; Nature; Organic Synthesis; Pattern; Pharmaceutical Preparations; Photoaffinity Labels; Plasma; Platelet Count measurement; Play; Preparation; Process; Production; Proteins; Proteomics; Public Health; Records; Regulation; Research; Research Personnel; Research Proposals; Research Training; Resources; Role; SECTM1 gene; Signal Transduction; Stream; Structure; Structure-Activity Relationship; Sulfate; Surface Plasmon Resonance; Therapeutic; Therapeutic Agents; Thrombocytopenia; Thrombopoiesis; Thrombosis; United States National Institutes of Health; Validation; X-Ray Crystallography; analog; analytical ultracentrifugation; base; biomacromolecule; biophysical analysis; biophysical techniques; career; career development; chemical property; computer studies; experience; functional mimics; high throughput screening; in vivo; innovation; member; mimetics; molecular modeling; novel; prevent; primary outcome; promoter; receptor; scaffold; screening; skills; small molecule; small molecule libraries; stem; sugar; therapeutic development; three dimensional structure

PROJECT SUMMARY Title: Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis. Key Words: Platelets, Glycosaminoglycans, thrombopoiesis, G6b-B, NSGMs The Candidate is an NIH K12 postdoctoral scholar on an academic career path. His focus is on the roles of glycosaminoglycans (GAGs) in thrombopoiesis. He has significant research experience studying GAG–protein interactions, and a strong background in organic synthesis notably, the preparation of aromatic-scaffold-based GAG mimetics known as non-saccharide GAG mimetics (NSGMs), which are functional mimics of GAGs. Career Development Plan: This proposal is well structured and involves 2 years of mentored research training, which will ensure that the candidate develops advanced research skills critical for an independent academic career. He has assembled an advisory committee of experienced and well-funded PIs, with proven track records of mentoring young academic researchers. He also has a well-resourced environment for the proposed research. Research Plan: The number of circulating platelets is tightly balanced through continuous production and removal of platelets to prevent potentially detrimental thrombosis. Platelets are produced through sequential processes, wherein hematopoietic stem cells commit to the formation of megakaryocytes (megakaryopoiesis), which release cytoplasmic extensions into the blood stream to produce platelets (thrombopoiesis). While some mechanisms and molecular regulators of these process have been identified, much remains to be elucidated. Of these, the roles of extracellular matrix and GAGs are poorly characterized. Although GAGs are regulators of various proteins, their heterogeneous nature and the challenges associated with obtaining homogeneous forms of these complex biomacromolecules remain bottlenecks for elucidating their biological roles. Our lab has developed a diverse chemical library of NSGMs which possess an aromatic scaffold carrying multiple sulfate groups mimicking the sulfated sugar scaffold of GAGs. NSGMs bind and selectively modulate several GAG- binding proteins involved in diseases, and thus serve as excellent chemical biology probes of GAG function. We have identified G4.1, a flavonoid-based NSGM as having potent thrombopoietic potential in vitro and in vivo. Our preliminary studies show that G4.1 binds with high affinity to G6b-B, an inhibitory receptor found on megakaryocytes and platelets, involved in the regulation of platelet production. Our studies also show that G4.1 promotes G6b-B dimerization, which is required for downstream signaling. Based on this data, we hypothesize that, G4.1 promotes thrombopoiesis, in part, by its highly selective interaction with G6b-B. We will determine the nature of the interaction of G4.1 with G6b-B, probe the selectivity of G4.1 for G6b-B, and elucidate the structure- activity-relationship (SAR) of this class of compounds. This research proposal benefits from; 1) the candidate’s personal track-record, 2) robust preliminary data, 3) a highly experienced advisory committee with relevant expertise to the proposed research, and 4) a supportive and well-resourced research environment. The three aims of the proposal are : I) Determine the nature of interaction of G4.1 with G6b-B, II) Evaluate the selectivity of G4.1 recognition of G6b-B, and III) Synthesize a library of G4.1 analogs and elucidate SAR.

项目摘要 标题：合成糖胺聚糖的模拟物作为巨核和血小板的调节剂。 关键词：血小板，糖胺聚糖，血栓形成，G6B-B，NSGMS 该候选人是NIH K12在学术职业道路上的博士后科学。他的重点是 血小板中的糖胺聚糖（插科打）。他具有研究堵嘴 - 蛋白质的重要​​研究经验 相互作用，以及有机合成的强大背景，尤其是基于芳族折线的制备 GAG模拟物被称为非含糖GAG MIMETICS（NSGMS），它们是GAG的功能模仿。职业 发展计划：该建议结构良好，涉及2年的指导研究培训，这是 将确保候选人发展对独立学术职业至关重要的高级研究技能。 他组建了一个由经验丰富且资金充足的PI组成的咨询委员 指导年轻的学术研究人员。他还为拟议的研究设有资源良好的环境。 研究计划：通过连续生产和 去除血小板以防止潜在的有害血栓形成。血小板是通过顺序产生的 过程，其中造血干细胞致力于形成巨核细胞（Megakaryopiesis）， 这将细胞质延伸释放到血流中以产生血小板（血小板）。而有些 这些过程的机制和分子调节剂已被鉴定出来，还有很多待阐明。的 这些，细胞外基质和插科打的作用的特征很差。尽管插科打s是 各种蛋白质，它们的异质性以及与获得均质形式相关的挑战 在这些复杂的生物百易分子中，仍然是阐明其生物学作用的瓶颈。我们的实验室有 开发了一个多元化的NSGMS化学库，该库具有携带多个硫酸盐的芳香族脚手架 模仿插科打糖的糖支架的组。 NSGM结合并选择性调制几个GAG- 涉及疾病的结合蛋白，因此是GAG功能的极好的化学生物学问题。我们 已经确定了基于类黄酮的NSGM的G4.1是在体外和体内具有潜在的血小板潜力。我们的 初步研究表明，G4.1与G6B-B高亲和力结合，G6B-B是一种抑制受体。 巨核细胞和血小板，参与血小板产生的调节。我们的研究还表明G4.1 促进g6b-b二聚化，这是下游信号传导所必需的。基于这些数据，我们假设 这是G4.1通过与G6B-B高度选择性的相互作用来促进血小板的。我们将确定 G4.1与G6B-B相互作用的性质，探测G4.1对G6B-B的选择性，并阐明结构 这类化合物的活动关系（SAR）。这项研究提案受益于； 1）候选人 个人曲目纪录，2）强大的初步数据，3）一个经验丰富的咨询委员会 拟议研究的专业知识，以及4）支持且资源丰富的研究环境。三个 该提案的目的是：i）确定G4.1与G6B-B的相互作用的性质，ii）评估选择性 G4.1识别G6B-B和III）合成了G4.1类似物的库并阐明SAR。