TGF beta Receptors and Cell Proliferation

描述（由申请人提供）：转化生长因子β（TGF-？）生物学是相同的生长因子如何能够诱导诸如生长刺激（即，间充质细胞）和生长抑制（即，上皮细胞）？考虑到TGF-？在许多正常和病理条件下，如果我们希望制定具体的干预战略，解决这个问题是至关重要的。为此，我们一直在调查的一般假设，TGF-？刺激细胞类型特异性信号通路作为调节这些表型的手段。一个在协调促纤维化（即，间充质），与生长抑制剂（即，上皮），细胞反应TGF-？PI3K在上一个融资周期，我们已经表明，PI 3 K代表一个分支点，在Smad独立的TGF-？信号传导，使得一个臂导致Pak 2和c-Abl的激活，而另一个臂与Akt和mTOR偶联。由于这一发现导致了一项多中心II期临床试验，测试甲磺酸伊马替尼与安慰剂治疗特发性肺纤维化的疗效，我们将使用各种生化，生物学和形态学方法在竞争性更新中扩展这些概念。首先，我们将确定的机制（S），其中TGF-？mTOR的激活刺激基质细胞增殖。建议在TGF-？通过抑制PI 3 K下游的Pak 2/c-Abl和Akt/mTOR分支来驱动组织纤维化。第二，鸟嘌呤核苷酸交换因子（GEF）磷酸化和受体协会在指导TGF-？将定义靶特异性和受体活化。第三，已确定的候选蛋白质调节成纤维细胞特异性TGF-？信号传导，提出实验来确定分别在上皮细胞和间充质细胞中阻止或促进这些途径活化的机制。这些问题的答案是至关重要的，如果进程介导细胞类型特异性TGF-？信令将被阐明。 与公共卫生的相关性（外行语言）：TGF-？是一种对人体健康有益或有害的蛋白质。虽然其刺激细胞生长的能力对于正常伤口愈合是重要的，但当不加抑制时，许多器官的功能可能被瘢痕破坏（即，纤维化）形成。拟定的研究将确定/表征可用于增加或减少该反应的靶点。

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-? has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that TGF-? stimulates cell type-specific signaling pathways as a means to regulate these phenotypes. One target with a critical role in coordinating the profibrogenic (i.e., mesenchymal), in contrast to the growth inhibitory (i.e., epithelial), cellular response to TGF-? is PI3K. During the previous funding cycle we have shown that PI3K represents a branchpoint in Smad-independent TGF-? signaling such that one arm leads to activation of Pak2 and c-Abl, while the other is coupled to Akt and mTOR. As this former finding has led to a multi-center Phase II clinical trial testing the efficacy of imatinib mesylate vs. placebo in the treatment of idiopathic pulmonary fibrosis, we will extend these concepts in the competing renewal using a variety of biochemical, biological, and morphologic approaches. First, we will determine the mechanism(s) by which TGF-? activation of mTOR stimulates stromal cell proliferation. It is proposed that greater efficacy and lower toxicity can be obtained in models of TGF-? driven tissue fibrosis by inhibiting both Pak2/c-Abl and Akt/mTOR branches downstream of PI3K. Second, the role of guanine nucleotide exchange factor (GEF) phosphorylation and receptor association in directing TGF-? target specificity and receptor activation will be defined. Third, a candidate protein has been identified which regulates fibroblast-specific TGF-? signaling, experiments are proposed to determine the mechanism(s) which prevents or promotes activation of these pathways in epithelial and mesenchymal cells, respectively. Answers to these questions are critical if the processes mediating cell type-specific TGF-? signaling are to be elucidated. Relevance to public health (lay language): TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. The proposed studies will identify/characterize targets which can be used to either increase or decrease this response.