Researchers Win $2.8 Million to Unravel Cell Basics Linked to Disease

By Madeline McCurry-Schmidt

Mutations in a meshwork of proteins at the outer edge of the cell nucleus, called the nuclear lamina, have been linked to many diseases—from muscular dystrophies and heart disorders to type 2 diabetes and premature aging.

Now, scientists at The Scripps Research Institute (TSRI) are on a mission to explore the nuclear lamina in new ways with the support of a grant of more than $2.8 million from the National Institutes of Health (NIH) Common Fund.

“We have to understand, in detail, the composition of the lamina and its underlying protein interaction network, so we can develop therapies for these diseases,” said TSRI Professor Larry Gerace, who will lead the new five-year project, in which Gerace’s group will work closely with the laboratory of TSRI Professor John R. Yates. The project is part of the NIH Common Fund’s 4D Nucleome program, which aims to shed light on how cells organize their genetic material and how this organization changes in different cell types and affects gene expression over time.

The nuclear lamina (Latin for “thin sheet of material”) is a network of fibrous proteins sandwiched between the membrane that forms the cell’s nuclear boundary and the thread-like, DNA-containing chromosomes that occupy the interior of the nucleus. Proteins associated with chromosomes attach to the nuclear lamina, ensuring the chromosomes are placed in the right order.

For many years, scientists believed the nuclear lamina was involved strictly in nuclear organization, but research in the 1990s revealed a connection to disease and suggested more extensive functions. Mutations in the nuclear lamina’s “lamin” proteins and the membrane proteins attached to nuclear lamins can somehow alter the functioning of specific cell types such as muscle and fat or the ability of stem cells to form these differentiated cells.

“We still don’t understand the most fundamental molecular basis for how these mutations lead to disease,” said Gerace.

With the new grant, the researchers hope to solve that mystery.

Gerace and his colleagues will isolate the nuclear lamina and associated chromatin from muscle and fat cells, as well as precursor stem cells, and with Yates lab, analyze how the nuclear lamins, nuclear membrane proteins and their cellular neighbors interact to create the nuclear lamina’s meshwork and to organize and regulate chromosomes. The researchers will rely on new technologies, developed in the Yates lab, to capture high-resolution data on protein interactions.

The number of the grant is 1U01DA040709.

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