NIGMS Invests in Scientific Grand Opportunities with Recovery Act Funds

The National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health (NIH), is investing $42.3 million for grants in scientific areas it identified as "Grand Opportunities (GO)." NIH developed the GO grant program to stimulate biomedical research and the economy using funds provided by the American Recovery and Reinvestment Act (Recovery Act).

Locally, a $1.3 million grant has been awarded to Dr. Jeffrey MacKeigan of the VanAndel Institute. He will study colon cancer cells' genetic makeup and how they develop a resistance to chemotherapy, with a view to more effective treatment of this disease. Colon cancer kills some 50,000 people a year. MacKeigan says, "92% of colon cancer patients do not live more than five years" (GR Press). He believes his research may significantly affect these outcomes. MacKeigan also says that outcomes for other cancers (ovarian and breast, for instance) may be affected by this research study.

"The GO grants fund projects that promise to have a significant impact on a field of biomedical science over two years," said NIGMS Director Jeremy M. Berg, Ph.D. "By closing specific knowledge gaps, creating new technologies, or building community-wide resources, these awards will dramatically propel progress in key scientific fields with a one-time investment."

The Recovery Act grants will also contribute to the economic recovery by creating jobs for researchers, technical and support staff, the makers of scientific equipment and others across the country. States receiving GO grants are: Arkansas, California, Iowa, Kentucky, Maryland, Massachusetts, Michigan, North Carolina, Pennsylvania, Texas, Tennessee, Washington and Wisconsin.

The GO grants include a broad range of projects. Several establish new databases, service centers or other resources that will be accessible to the entire scientific community, advancing biomedical research — and possibly medical care — for years to come. Others tackle large projects, such as understanding the activity of all the genes in human white blood cells, which require the collaborative work of dozens of scientists.

NIGMS has awarded 14 GO grants to scientists in 13 states.

Details about MacKeigan's grant

Project Number:  1R01CA138651-01A1   
Title: MK-STYX: A REQUISITE GATEKEEPER TO MITOCHONDRIAL FUNCTION AND DEATH 

Abstract Text:
DESCRIPTION (provided by applicant): Chemoresistant metastatic disease presents the most serious threat to cancer patients despite the increased arsenal of targeted therapeutic options available to clinicians. While intense study into late-stage cancer progression has revealed a number of mechanisms that contribute to chemoresistance, little is known about the intracellular signaling mechanisms that desensitize cells to cytotoxic chemotherapy. In an effort to address this knowledge gap, we recently performed a large-scale RNA-interference (RNAi) screen intended to comprehensively identify critical kinases and phosphatases in the human genome that alter or modify tumor cell sensitivity to chemotherapeutic agents. In this RNAi screen, we identified a novel phosphatase, MK-STYX, which potently suppressed the response of tumor cells to a wide variety of chemotherapeutic drugs. Our central hypothesis is that MK-STYX specifically controls mitochondrial function by regulating phosphorylation of the machinery required for ATP synthesis, and thereby serves an essential role in the induction of chemotherapeutic-induced cell death. The objective of this project is to determine how MK-STYX regulates cellular ATP levels, and thus modulates intrinsic apoptosis. We propose the following specific aims to address this hypothesis and to understand its significance in the context of metastatic colorectal carcinoma: (1) Identify the catalytic mechanism of MK-STYX in the mitochondria; (2) Identify the mechanism whereby MK-STYX regulates chemoresistance; (3) Establish the role of MK-STYX in colorectal cancer progression and chemoresistance. Consistent with our central hypothesis, we have shown that loss of MK-STYX increases ATP production. Therefore, we predict that the elevation in cellular ATP due to loss of MK-STYX is sufficient to inhibit apoptosome formation and entry into apoptosis. We have shown that MK-STYX interacts with two additional mitochondrial proteins and we will mechanistically determine the mitochondrial function and the molecular consequences of each of these interactions. We have also shown that loss of MK-STYX expression correlates with colorectal cancer progression. To determine whether loss of MK-STYX mediates chemoresistance in vivo, we will test the efficacy of standard chemotherapies on a colorectal xenograft model using cell lines that demonstrate variable expression of MK-STYX, or have been manipulated to decrease endogenous MK-STYX levels. We will also determine the prognostic significance of MK-STYX protein levels in a cohort of patients with colorectal cancer. PUBLIC HEALTH RELEVANCE: Our recent identification of thirteen phosphatases that suppress chemoresistance, or whose expression drives chemosensitivity, has provided an avenue for a better understanding of the molecular basis of chemoresistance. If we can determine how loss of expression of these phosphatases leads to the development of chemoresistance, we will be better able to screen for chemoresistance and design rational drug strategies to treat chemoresistant tumors in cancer patients.

from http://projectreporter.nih.gov/project_info_description.cfm 

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