Characterization of a Novel Growth and Survival Factor for Human Mast Cells

描述(由申请人提供)：肥大细胞是多种炎症性疾病状态的重要效应者。虽然组织肥大细胞数量的增加是哮喘、关节炎和纤维化疾病的一贯特征，但除了干细胞因子(SCF)及其受体c-kit的结构性输入之外，关于加速肥大细胞生长或维持其生存的机制尚不清楚。我们已经初步确定了一种有效的人类肥大细胞生长因子，它是由人类肥大细胞株自发分泌的。它在功能上与干细胞因子不同，并使原代人类肥大细胞对传统的c-kit抑制剂具有耐药性。这项建议的目的是分离和纯化该因子，确定其氨基酸序列，并开发所需的探针和抗体，以确定其在严重哮喘患者的大量支气管活检组织中的表达部位及其与肥大细胞增殖的关系。鉴于肥大细胞的重要性，以及关于人类肥大细胞发育控制机制的有限知识，这些研究具有直接的翻译和治疗意义。

DESCRIPTION (provided by applicant): Mast cells are important effectors in a wide array of inflammatory disease states. Although increases in the numbers of tissue mast cells are a consistent feature of asthma, arthritis, and fibrotic diseases, there is little known about the mechanisms that accelerate mast cell growth or sustain their survival beyond the constitutive input from stem cell factor (SCF) and its receptor, c-kit. We have preliminarily characterized a potent growth factor for human mast cells that is secreted spontaneously by a human mast cell line. It is functionally distinct from SCF, and renders primary human mast cells resistant to conventional c-kit inhibitors. The goal of this proposal is to isolate and purify the factor, determine its amino acid sequence, and develop the probes and antibodies needed to determine its sites of expression and its relationship to mast cell hyperplasia in a large collectin of bronchial biopsies from human subjects with severe asthma. Given the importance of mast cells and the limited body of knowledge regarding the mechanisms that control their development in humans, these studies have direct translational and therapeutic implications.