Novel Mechanisms of C-Kit Regulation in Mast Cells

肥大细胞中 C-Kit 调节的新机制

• 批准号: 7571626
• 负责人: Reuben Kapur
• 金额: $ 36.68万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571626
• 关键词: Amino Acid Sequence; Asthma; Bacterial Infections; Biochemical Pathway; Biology; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Chronic; Coronary Arteriosclerosis; Coronary artery; Cytokine Receptors; Data; Development; Differentiation and Growth; Disease; Exhibits; Future; Genetic; Goals; Growth; Human; Hypersensitivity; IgE Receptors; Immunity; In Vitro; Inflammation; Ligands; Malignant Neoplasms; Mediating; Molecular; Molecular Target; Multiple Sclerosis; Mus; Mutation; Natural Immunity; Pathway interactions; Phase; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Production; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Regulation; Research Personnel; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Stem Cell Factor; Testing; Work; base; cell growth; cytokine; design; expectation; gain of function mutation; genetic manipulation; in vivo; innovation; insight; mast cell; mastocytosis; migration; mortality; mutant; novel; pathogenic bacteria; receptor; reconstitution; response; src-Family Kinases; transcription factor

Mast cell activation plays a critical pathophysiologic role in asthma and allergy. A role for mast cell activation has also been described in multiple sclerosis, rheumatoid arthritis and coronary artery disease. However, recent studies challenge the dogma of a pathological role for mast cell activation, demonstrating its prominent role in the early phases of innate immunity to pathogenic bacteria. These observations make our understanding of mast cell biology more crucial than ever. While several cytokines influence the growth, survival, and maturation of mast cells, stem cell factor (SCF) and its interaction via the tyrosine kinase receptor, c-Kit is essential for normal mast cell development and function. Mice deficient in the expression of c-Kit lack mast cells and exhibit enhanced mortality to induced bacterial infections. Thus, although an important role for c-Kit and IgE receptor initiated signals in regulating normal development and function of mast cells has been demonstrated, the signaling pathways downstream from these receptors that regulate these processes are poorly understood. Identification of key intracellular signaling molecules and pathways involved in regulating the development and function of mast cells via these receptors will facilitate the design of specific molecular therapies for the treatment of mast cell disorders, including human mastocytosis associated with gain-of-function mutations of c-Kit, chronic inflammation, allergy as well as for promoting immunity to bacterial infections. Our long-range goal is to understand the signaling mechanism(s) that control mast cell functions downstream from cytokine receptors as well as immunoreceptors. The objective of this application is to determine how SHIP phosphatase, Lyn Src family kinase and p85 regulatory subunits (a and (3) of class IA PI-3Kinase interact to regulate mast cell differentiation, growth/survival as well as cytokine production and degranulation. The central hypothesis of this application, which has been formulated on the basis of our preliminary data, is that Lyn kinase is critical for the activation of SHIP phosphatase in mast cells. In the absence of SHIP phosphorylation (due to lack of Lyn expression) mast cells demonstrate hypersensitivity to SCF-induced survival, growth and differentiation as well as enhanced IgE receptor induced degranulation and cytokine production. These phenotypes are due to hyperactivation of the PI-3Kinase/Aktpathway. Furthermore, p85ct and p85|3 regulatory subunits of class IA PI-3Kinase play quantitatively distinct roles in regulating mast cell functions. These differences are due to the presence of unique amino terminal sequences in p85a vs (p85|3). Our proposed studies will provide unique insights into the physiologic significance of the in vivo interactions between SHIP, Lyn and p85 regulatory subunits of class IA PI-3Kinase in regulating all aspects of mast cell biology.

肥大细胞激活在哮喘和过敏中起关键的病理生理作用。肥大细胞激活的作用 还在多发性硬化症，类风湿关节炎和冠状动脉疾病中描述了。然而， 最近的研究挑战了肥大细胞激活的病理作用的教条，证明了其 在对致病细菌的先天免疫的早期阶段中的重要作用。这些观察使我们 了解肥大细胞生物学比以往任何时候都更为重要。虽然几种细胞因子会影响增长，但 肥大细胞，干细胞因子（SCF）及其通过酪氨酸激酶的相互作用的存活和成熟 受体，C-KIT对于正常的肥大细胞发育和功能至关重要。小鼠表达不足 C-Kit缺乏肥大细胞，并且对诱导细菌感染的死亡率增强。因此，虽然是 C-KIT和IgE受体引发信号的重要作用在调节正常发育和功能中 已经证明了肥大细胞，这些受体下游的信号传导途径调节 这些过程知之甚少。识别关键细胞内信号分子和途径 参与通过这些受体调节肥大细胞的发育和功能将有助于设计 用于治疗肥大细胞疾病的特定分子疗法（包括人肥大症） 与C-KIT，慢性炎症，过敏以及促进功能的功能增强突变有关 对细菌感染的免疫力。 我们的远程目标是了解控制桅杆功能的信号传导机制 来自细胞因子受体以及免疫感受器的下游。该应用的目的是 确定载磷酸酶，Lyn SRC家族激酶和p85调节亚基（a和（3）类IA类 PI-3激酶相互作用以调节肥大细胞分化，生长/生存以及细胞因子的产生和 脱粒。该应用的中心假设，已根据我们的 初步数据是，Lyn激酶对于肥大细胞中船磷酸酶的激活至关重要。在 缺乏船磷酸化（由于缺乏LYN表达）肥大细胞表现出对 SCF诱导的生存，生长和分化以及IgE受体诱导的脱粒 和细胞因子产生。这些表型是由于PI-3Kinase/aktPathway的过度激活引起的。 此外，p85ct和p85 | 3级IA pi-3kinase的调节亚基在定量上扮演着不同的角色 调节肥大细胞功能。这些差异是由于存在独特的氨基终端 p85a vs中的序列（p85 | 3）。我们提出的研究将为生理学提供独特的见解 IA Pi-3kinase类体内相互作用的重要性 在调节肥大细胞生物学的各个方面。