Identifying the mechanisms through which calcineurin regulates proportional growth control.

所有的生物体都能生长出与其身体相关的特定比例的器官和附属物，而那些再生器官和附属物的动物也能将它们再生到与丢失的原始结构完全相同的尺寸。在发育和再生过程中，器官和附属物的协调生长涉及在与身体不成比例的生长速率（异源）和与身体成比例的生长速率（等轴）之间切换。虽然已知细胞生物学、激素、生长因子和细胞周期调节的许多方面有助于与组织生长相关的细胞增殖，但仍不清楚这些机制如何协调以产生与身体相关的器官和附属物的成比例生长。我的小组发现，在斑马鱼鳍再生过程中，钙调节磷酸酶钙调神经磷酸酶的抑制导致它们失去比例生长控制，而在未截肢的鳍中，钙调神经磷酸酶的抑制将它们的等长生长转换为异速生长。虽然已知存在生长控制的全身和局部调节剂，但不知道如何调节或整合这些调节剂以控制多组织结构的成比例生长。因此，我的Eigene Stelle（临时PI）提案的目标是定义钙调节磷酸酶钙调神经磷酸酶如何整合到细胞生物学和分子机制中，这些机制决定组织祖细胞何时生长和停止生长以保持与身体的比例关系。为了实现这一目标，我将确定：1）哪些细胞介导钙调神经磷酸酶调节的比例生长; 2）哪些下游分子机制介导钙调神经磷酸酶调节的比例生长; 3）哪些分子机制（Ca 2+介导和Ca 2+非依赖性）调节钙调神经磷酸酶以调节比例生长。

All organisms grow organs and appendages to specific proportions in relation to their bodies, and those animals that regenerate them do so to the exact same dimensions as the lost original structures. The coordinated growth of organs and appendages during development and regeneration involves switching between growth rates that are disproportional to the body (allomentric) and growth rates that are proportional the body (isometric). While many aspects of the cell biology, hormone, growth factor and cell cycle regulation contribute to the cell proliferation associated with tissue growth are known, it remains unclear how these mechanisms are coordinated to produce proportional growth of organs and appendages relation to the body. My group discovered that inhibition of the calcium-regulated phosphatase calcineurin during the regeneration of zebrafish fins causes their loss of proportional growth control and that calcineurin inhibition in unamputated fins switched their isometric growth to allometric growth. While it is known that there are body-wide and local regulators of growth control, it is not known how these are regulated or integrated to control proportional growth of multi-tissue structures. Therefore, the goal of my Eigene Stelle (Temporary PI) proposal is to define how the calcium-regulated phosphatase calcineurin is integrated into the cell biology and molecular mechanisms that determine when tissue progenitor cells are to grow and to stop growing to maintain the proportional relationship to the body. To achieve this goal, I will determine: 1) which cell(s) mediates calcineurin-regulated of proportional growth; 2) what downstream molecular mechanisms mediate calcineurin-regulated proportional growth; 3) which molecular mechanisms (both Ca2+-mediated and Ca2+-independent) are regulating calcineurin to regulate proportional growth.