Growth regulation by the Fat signaling pathway

脂肪信号通路的生长调节

• 批准号: 9479202
• 负责人: KENNETH D IRVINE
• 金额: $ 28.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9479202
• 关键词: Affect; Binding; Biochemical; Biomechanics; Brain; Breast; Cell Proliferation; Cell division; Cells; Congenital Abnormality; Development; Diagnosis; Disease; Drosophila genus; Epithelial Cells; Fatty acid glycerol esters; Feedback; Genetic; Genetic study; Genomics; Goals; Growth; Health; Human; Image; Intestines; Investigation; Joints; Kidney; Link; Liver; Lung; Malignant Neoplasms; Mammalian Cell; Mechanics; Membrane; Mitotic spindle; Molecular; Organ; Organ Size; Organism; Organogenesis; Ovary; Pathway interactions; Pattern; Phosphotransferases; Play; Process; Prostate; Protein Isoforms; Proteins; RNA interference screen; Regenerative Medicine; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Skin; Stem cells; Tissues; Van Maldergem syndrome; Wing; ZYX gene; cancer type; cell behavior; experimental study; genetic manipulation; girls; imaging genetics; imaging study; in vivo; insight; mathematical model; mechanical force; mechanotransduction; morphogens; novel; organ growth; planar cell polarity; polarized cell; public health relevance; repaired; ubiquitin ligase; vector

 DESCRIPTION (provided by applicant): The goal of this proposal is to determine how growth and polarity are regulated in developing tissues to form organs of appropriate size and shape. We will investigate two processes that play fundamental yet incompletely understood roles in controlling organ size and shape: Ds-Fat signaling and cytoskeletal tension. A remarkable feature of Ds-Fat signaling is that it can be regulated by the vector and slope of Dachsous (Ds) and Four-jointed (Fj) gradients to influence distinct downstream processes that control planar cell polarity (PCP) and, through regulation of Hippo signaling, growth. These gradients polarize Fat activity within cells, as can be visualized by the polarization of the Fat signaling component Dachs. Characterization of this pathway will provide novel insights into the control of cell behavior, and how patterning and growth can be linked during development. It has also been proposed that mechanical forces could play roles in modulating organ size and shape, but the mechanisms by which this occurs are not well understood. Recent studies however, including our characterization of the regulation and role of the Jub protein, have implicated the Hippo signaling pathway in regulation of growth by mechanical forces. The studies proposed here will enhance molecular understanding of how patterning, e.g. as provided by morphogen gradients, directs organogenesis, how mechanical forces within and between cells modulate organogenesis, and how these biochemical and biomechanical processes are integrated. The first aim proposes studies to define molecular mechanisms that control the accumulation and polarity of the key Fat signaling component Dachs. The second aim will focus on defining mechanisms by which Dachs and other factors influence planar cell polarity, including both tension-dependent and tension-independent processes. The third aim investigates molecular mechanisms that regulate the key Hippo pathway kinase Warts to control growth, and interrelationships among growth-regulatory processes that affect Warts. The proposed studies will provide a deeper understanding of mechanisms that control tissue polarity, and that control growth through Hippo signaling. Organ shape is crucial for normal organ function, and specific requirements for Ds-Fat signaling in humans have been revealed by its association with Van Maldergem syndrome. As inappropriate growth during development results in organs that are incorrectly sized or shaped, it can cause birth defects. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in mature organisms results in cancer. Cancers in a wide variety of organs have been associated with inactivation of Hippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate Understanding the regulation of Hippo signaling is thus relevant to a range of human health issues, including birth defects, cancer, and regenerative medicine.

 描述（由申请人提供）：该提案的目标是确定在发育组织中如何调节生长和极性以形成适当大小和形状的器官。我们将研究在控制器官大小和形状方面发挥基本但尚未完全了解的作用的两个过程：Ds-Fat 信号传导和细胞骨架张力。 Ds-Fat 信号传导的一个显着特征是，它可以通过 Dachsous (Ds) 和四关节 (Fj) 梯度的矢量和斜率进行调节，以影响控制平面细胞极性 (PCP) 的不同下游过程，并通过调节 Hippo 信号传导来影响生长。这些梯度使细胞内的脂肪活动极化，这可以通过脂肪信号成分 Dachs 的极化来观察。该途径的表征将为细胞行为的控制以及发育过程中图案形成和生长如何联系起来提供新的见解。也有人提出机械力可以在调节器官大小和形状方面发挥作用，但其发生机制尚不清楚。然而，最近的研究，包括我们对 Jub 蛋白的调节和作用的表征，表明 Hippo 信号通路与机械力调节生长有关。 这里提出的研究将增强分子对图案如何形成的理解，例如。由形态发生素梯度提供，指导器官发生、细胞内和细胞间的机械力如何调节器官发生，以及这些生化和生物力学过程如何整合。第一个目标是提出研究来定义控制关键脂肪信号成分 Dachs 积累和极性的分子机制。第二个目标将侧重于定义 Dachs 和其他因素影响平面细胞极性的机制，包括张力依赖性和张力无关过程。第三个目标是研究调节关键 Hippo 通路激酶疣以控制生长的分子机制，以及影响疣的生长调节过程之间的相互关系。 拟议的研究将更深入地了解控制组织极性以及通过 Hippo 信号传导控制生长的机制。器官形状对于正常器官功能至关重要，人类 Ds-Fat 信号传导的特殊要求已通过其与 Van Maldergem 综合征的关联而揭示。由于发育过程中的生长不当会导致器官大小或形状不正确，从而可能导致出生缺陷。控制器官生长也很重要 了解干细胞如何用于修复或替换受损器官，这是再生医学的目标。此外，无法限制成熟生物体的生长会导致癌症。多种器官中的癌症都与 Hippo 信号传导失活有关，包括肝脏、肾脏、皮肤、大脑、肠、肺、卵巢、乳腺癌和前列腺。因此，了解 Hippo 信号传导的调节与一系列人类健康问题相关，包括出生缺陷、癌症和再生医学。