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

描述（由申请人提供）：肥大细胞在多种炎症疾病状态中是重要的效应器。尽管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致特征，但除了干细胞因子（SCF）及其受体c-kit的组成输入外，关于加速肥大细胞生长或维持其存活的机制知之甚少。我们初步鉴定了一种由人肥大细胞系自发分泌的人肥大细胞的强效生长因子。它在功能上不同于SCF，并使原代人肥大细胞对传统的c-kit抑制剂产生耐药性。本提案的目标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，以确定其表达位点及其与严重哮喘患者大量支气管活检中肥大细胞增生的关系。考虑到肥大细胞的重要性和人类控制肥大细胞发育机制的有限知识，这些研究具有直接的转化和治疗意义。

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.