权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Polymer Approaches to Receptor Activation and Inhibition

受体激活和抑制的聚合物方法

基本信息

批准号：
10795136
负责人：
NICOLE S SAMPSON
金额：
$ 6.48万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

项目摘要

Our laboratory will interrogate and/or block function in biological systems with functionalized polymers based on recent developments from our laboratory that provide insights into how to control binding and activation of receptors, and into control of ruthenium-catalyzed metathesis copolymerizations. First, cholera is still a life- threatening illness with an annual incidence of ~2.9 million cases and ~95,000 deaths annually in endemic countries. Many outbreaks of cholera would be staunched by a therapeutic that reduced cell binding and thus spreading of V. cholerae, the etiologic agent. Our laboratory and collaborators demonstrated that cholera toxin B pentamer (CTB) and a norbornyl polymer randomly displaying galactose and fucose self-assemble into cross- linked CTBn–glycopolymer networks. Larger aggregates result in better inhibition of cholera intoxication. Synthesis of different fucose/galactose polymer systems, analysis of the dependence of aggregation capture and kinetics on polymer structure, in combination with toxicity testing will be undertaken to develop simple, oral therapeutics for cholera disease. Second, about 12% of American males between the ages of 15-44 are infertile or subfertile, and failure of sperm to undergo acrosomal exocytosis (AE) is responsible for a significant fraction. Better molecular diagnostics are required to diagnose subfertility. We demonstrated that human and mouse sperm acrosomal exocytosis (AE) are activated with glycopolymers, although highly cooperative inhibition of AE is observed at higher concentrations of the dose-response curve. Polymers with different backbones, sugar densities, and sugars will be utilized to reduce cooperativity in the inhibition arm and to analyze which are best for activation of human AE. The most effective probes will be used to identify the human AE sperm receptor. Third, copolymers with well-controlled microstructure display superior morphology and enhanced properties, such as spatial organization, folding and self-assembly. We demonstrated that precisely alternating AB copolymers can be prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamides (A) and large unstrained cycloalkenes (B) with Grubbs III catalyst through alternating ring-opening metathesis polymerization. The A monomer substituent and the microsequence of the polymer define surface behavior and solution structure morphologies. Mechanistic structure-activity studies with A monomer varying C7 substituents (ketone, ester, methenyl) will be undertaken to understand the source of alternating selectivity with an expanded B monomer repertoire. These SAR studies will allow further exploitation of AROMP for gradient copolymer synthesis to tune material properties and functions in one-pot polymerization reactions. The underlying chemical synthetic methodologies proposed for these three discrete projects are highly related through polymer synthesis. We anticipate synergy and support between project researchers will provide further opportunities for innovation that cross between projects.

我们的实验室将询问和/或阻断生物系统中的功能与功能化聚合物的基础上，我们实验室的最新进展提供了如何控制结合和激活的见解，受体，并控制氯铵催化的复分解共聚。首先，霍乱仍然是一种生命- 威胁性疾病，每年发病约290万例，每年约95，000例死亡，国家许多霍乱的爆发可以通过减少细胞结合的治疗方法来阻止，传播霍乱弧菌，病原体。我们的实验室和合作者证明霍乱毒素 B五聚体（CT B）和随机展示半乳糖和岩藻糖的乙酰基聚合物自组装成交叉- 连接的CTBn-糖基共聚物网络。聚集体越大，对霍乱中毒的抑制作用就越好。不同岩藻糖/半乳糖聚合物体系的合成，聚集捕获依赖性的分析和聚合物结构的动力学，结合毒性测试，将进行开发简单，口服霍乱的治疗方法其次，15-44岁的美国男性中，约有12%的人不育或生育力低下，精子不能进行顶体胞吐作用（AE）是造成很大比例的原因。需要更好的分子诊断来诊断生育力低下。我们证明了人类和老鼠精子顶体胞吐作用（AE）被糖聚合物激活，尽管AE的高度协同抑制在剂量-反应曲线的较高浓度下观察到。具有不同主链的聚合物，糖密度和糖将被用来减少抑制臂的协同性，并分析哪一个是最好的用于激活人类AE。最有效的探针将用于鉴定人AE精子受体。第三，具有良好控制的微结构的共聚物显示出上级形态和增强的性能，例如空间组织、折叠和自组装。我们证明了精确交替的AB 共聚物可以由双环[4.2.0]辛-6-烯-7-甲酰胺（A）和大的未应变的环烯烃（B）与Grubbs III催化剂通过交替开环易位聚合。的A 单体取代基和聚合物的微序列决定了表面行为和溶液结构形态学用A单体改变C7取代基（酮，酯，甲基）将进行了解来源的交替选择性与扩大B单体保留曲目。这些SAR研究将允许进一步利用AROMP进行梯度共聚物合成，以调整在一锅聚合反应中的材料性质和功能。潜在的化学合成物为这三个独立项目提出的方法通过聚合物合成而高度相关。我们预计项目研究人员之间的协同作用和支持将为创新提供进一步的机会，项目之间的交叉。