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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM106023-02S1
Application #
8893760
Study Section
Special Emphasis Panel (ZGM1-CBB-0 (MI))
Program Officer
Ainsztein, Alexandra M
Project Start
2013-06-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$62,999
Indirect Cost
$27,257
Name
Carnegie Institution of Washington, D.C.
Department
Type
DUNS #
072641707
City
Washington
State
DC
Country
United States
Zip Code
20005
Jiang, Hao; He, Xiaonan; Wang, Shusheng et al. (2014) A microtubule-associated zinc finger protein, BuGZ, regulates mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting. Dev Cell 28:268-81
Kochin, Vitaly; Shimi, Takeshi; Torvaldson, Elin et al. (2014) Interphase phosphorylation of lamin A. J Cell Sci 127:2683-96
Shimi, Takeshi; Goldman, Robert D (2014) Nuclear lamins and oxidative stress in cell proliferation and longevity. Adv Exp Med Biol 773:415-30
Guo, Yuxuan; Kim, Youngjo; Shimi, Takeshi et al. (2014) Concentration-dependent lamin assembly and its roles in the localization of other nuclear proteins. Mol Biol Cell 25:1287-97
Chen, Haiyang; Zheng, Xiaobin; Zheng, Yixian (2014) Age-associated loss of lamin-B leads to systemic inflammation and gut hyperplasia. Cell 159:829-43
Guo, Yuxuan; Zheng, Yixian (2013) Sculpting the nucleus with dynamic microtubules. Dev Cell 27:1-2