This proposal aims to study the structural organization of the different types of lamin networks/meshworks during interphase and mitosis using super resolution microscopy techniques.
In Aim 1, we plan to determine whether each lamin (LA, LC, LB1, LB2) forms a separate lamina meshwork or whether the establishment of a lamina meshwork requires the interactions of different lamin isoforms in normal interphase nuclei. We will also study the interactions of each of the lamins with chromatin and nuclear pore complexes (NPCs). As animal cells enter mitosis, parts of the interphase membrane network, including the nuclear lamina, and nuclear proteins re-organize into an inter-connected network that both surrounds and permeates the spindle microtubules. This network has been referred to as either the spindle envelope (or sheath) or spindle matrix. Here we will refer to the network as the Spindle envelope/matrix (Spenix). The major challenge in defining the function of the Spenix is to visualize the behavior of Spenix proteins and link their behaviors to their functions in mitosis.
In Aim 2, we will apply super resolution microscopy to study the membrane and protein organization of the Spenix, which should open the door to dissect not only the organization of the Spenix but also the functional relationship of the Spenix and the mitotic spindle. The results from the proposed studies will provide important new information regarding the interactions and functions of the nuclear lamins and their interactions with their major interacting partners in interphase and mitosis.
Although the study of many cellular structures have reached molecular details, the organization of the nuclear lamins in the interphase nuclear lamina and in the mitotic spindle envelope and matrix (Spenix) remain poorly defined. By applying newly developed super resolution microscopy techniques, this proposal addresses these areas of cell biology that have received very little attention. Considering the importance of the nuclear lamina and the Spenix in regulating cell proliferation, the results of the proposed studies will provide new insights into the many human diseases associated with the lamin mutations and will reveal new therapeutic targets for halting uncontrolled cell divisions in cancer.
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