PHYSICAL CHEMISTRY OF THERAPEUTIC PLASMA PROTEINS

我们建议继续研究它的结构、稳定性和分子。 选定的人血浆蛋白的相互作用。这些措施包括(1) 纤维连接蛋白是一种多结构域糖蛋白，它与许多 大分子并调节各种细胞与表面的附着， (2)补体C1，是一种大的多亚基组合，其激活可触发 复杂的宿主-防御反应，(3)C1-抑制物，一种蛋白酶抑制物 它调节活性C1的水平，以及(4)抗凝血酶III，另一个 凝血级联反应中几种蛋白水解酶的抑制剂。 光谱技术，特别是荧光技术将被用于 研究功能上的动力学和/或平衡方面 重要的蛋白质-蛋白质相互作用，如纤维连接蛋白/胶原， 纤维连接蛋白/肝素、C_1-抑制物/C_1及其各亚组分之间 氯(Clq、Clr和ClS)。这些相同的技术将被用于检测 并表征了这些蛋白质在响应于 各种形式的压力(热、变性剂、pH)。我们将努力 识别独立展开的结构域，并在可行的情况下将其隔离 从亲本蛋白的酶消化中提取并进一步鉴定它们 在稳定性和相互作用方面。差示扫描 量热法将用于热变性和结果的研究 将与在相同条件下进行的光谱测量相关 条件。我们将继续寻求治疗的条件 设计的血浆蛋白可以承受巴氏杀菌或其他处理 选择性地灭活潜在的感染性病原体(肝炎病毒， HTLV III)，可能会污染临床制剂。除了 更好地理解结构和功能，我们的研究可能会导致 确定新的交互，以更好地理解角色 这些蛋白质在病理条件下的稳定性和安全性的提高 从人体血浆中提取的输血产品。

We propose continued research into the structure, stability, and molecular interactions of selected human plasma proteins. These include (1) fibronectin, a multidomain glycoprotein which interacts with numerous macromolecules and mediates the attachment of various cells to surfaces, (2) complement C1, a large multisubunit assembly whose activation triggers an elaborate host-defense reaction, (3) C1-Inhibitor, a protease inhibitor which regulates the levels of active C1, and (4) antithrombin III, another inhibitor of several proteases in the blood clotting cascade. Spectroscopic techniques, especially fluorescence, will be used to investigate the kinetic and/or equilibrium aspects of functionally important protein-protein interactions such as fibronectin/collagen, fibronectin/heparin, C1-Inhibitor/C1 and between the various subcomponents of Cl (Clq, Clr, and Cls). These same techniques will be used to detect and characterize structural transitions of these proteins in response to various forms of stress (heat, denaturants, pH). Efforts will be made to identify independently unfolding domains and, where feasible, isolate them from enzymatic digests of the parent protein and further characterize them with respect to stability and interactions. Differential scanning calorimetry will be used in studies of thermal denaturation and results will be correlated with spectral measurements made under identical conditions. We will continue to seek conditions under which therapeutic plasma proteins can withstand pasteurization or other treatment, designed to selectively inactivate potentially infectious agents (hepatitis viruses, HTLV III) which might contaminate clinical preparations. In addition to a better understanding of structure and function, our studies may lead to the identification of new interactions, to a better understanding of the role of these proteins in pathological conditions and to the improved safety of transfusion products derived from human plasma.