- MDA has awarded more than $2.5 million in ALS-related research grants, effective Aug. 1, 2011, to scientists at labs in the United States and Canada.
- The newly funded ALS research projects tackle the functions of the TDP43, FUS, MCT-1 and AMPA receptor proteins; mitochondrial and immune system function; muscle atrophy; neuronal stress; and a possible combination drug treatment.
- Grants at a Glance is an online showcase highlighting new MDA research projects. Some 300 current MDA-funded research projects can be viewed in Active Research Grants.
MDA has awarded nine grants totaling more than $2.5 million to fund research projects focused on uncovering the causes of, and developing therapies for, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease).
The new grants went to investigators at labs in the United States and Canada.
The newly funded projects include research into:
- neuronal stress early in the ALS disease process using “bioluminescent mice”;
- a possible ALS combination drug treatment;
- the normal and abnormal functions of the TDP43, FUS, MCT-1 and AMPA receptor proteins;
- function and dysfunction in the mitochondria and the immune system; and
- molecular processes underlying muscle atrophy.
MDA's Board of Directors approved the new grants at its July meeting, based on recommendations from the Association's Scientific and Medical Advisory Committees (SAC and MAC). Grants are scored and recommended for approval based on the capabilities of the applicant, the scientific merit of the project, and the proposal's relevance to developing treatments for the diseases in MDA's program.
Of the nine new grants, five are research grants, awarded to independent investigators who direct their own research and that of others. The other four grants are development grants that support research conducted by scientists who are members of a research team and who study under the guidance of a principal investigator.
What do the new ALS grants cover?
Following is a listing of the ALS-related grants approved by MDA’s Board in July 2011:
Observing motor neuron stress in real time with bioluminescent mice
Jasna Kriz, associate professor in the department of psychiatry and neuroscience at Laval University, Quebec City, Canada, was awarded an MDA research grant totaling $445,086 over three years to help generate ALS imaging reporter mice.
These research models, with bioluminescent and fluorescent genes (from fireflies), will enable scientists to visualize, in live mice, different elements of the ALS disease process such as neuroinflammation and neuronal damage in the brain and spinal cord. The 3-dimensional representations will make it possible for scientists to make assessments over a period of time and in a noninvasive manner.
Identifying biomarkers for ALS associated with mutated FUS and TDP43
Clotilde Lagier-Tourenne, a postdoctoral fellow at the University of California, San Diego, in La Jolla, was awarded an MDA development grant totaling $180,000 over a period of three years. The funds are helping fund Lagier-Tourenne's study of the effects of ALS-causing mutations in two RNA binding proteins, TDP43 and FUS.
Abnormal function of these proteins appears to disrupt the processing of RNA (the chemical step that directs protein synthesis). Lagier-Tourenne and colleagues' proposed set of studies aims to identify clinically useful biomarkers for ALS associated with TDP43 and FUS mutations.
Testing a possible ALS combination drug therapy in mice
MDA awarded a research grant totaling $202,508 over three years to Raymond Grill, assistant professor in the department of integrative biology and pharmacology at the University of Texas Health Science Center in Houston.
Working with the SOD1 research mouse, Grill's research team is testing the hypothesis that a drug called Licofelone will enhance the ability of riluzole (Rilutek) to better penetrate the nervous system. (Rilutek is the only drug approved by the U.S. Food and Drug Administration for treatment of ALS, and slightly extends survival time. Licofelone has completed phase 3 testing in humans for osteoarthritis but is not yet FDA approved.)
The researchers expect the combination treatment will reduce inflammation, protect motor function, rescue motor neurons and prolong survival in the mice.
Determining whether mitochondrial dysfunction is a cause or consequence of motor neuron degeneration
MDA awarded a research grant totaling $429,983 over three years to Don Cleveland at the Ludwig Institute for Cancer Research in La Jolla, Calif. The funds are helping support Cleveland’s research into mitochondrial dysfunction and toxicity in the inherited SOD1-associated forms of ALS.
Cleveland is working to determine in which nervous system cell types mitochondrial damage occurs; whether the ensuing mitochondrial dysfunction is a cause or a consequence of neuronal degeneration; and if the effects are the same in various forms of SOD1-associated ALS caused by different SOD1 mutations.
Uncovering the mechanisms underlying muscle breakdown and atrophy
Alfred Goldberg, professor or cell biology at Harvard Medical School in Boston, received an MDA research grant totaling $410,777 over three years to support his ongoing research into the mechanisms underlying muscle atrophy.
In his previous work, Goldberg helped clarify the general mechanisms of muscle atrophy resulting from motor neuron disease, inactivity, various systemic diseases, and myopathies.
Goldberg and his research team will focus now on mechanisms that normally inhibit a protein called FoxO, which has been implicated in stimulating muscle protein breakdown.
Refining methods to block AMPA receptors, known to cause toxicity and motor neuron death
MDA awarded a research grant totaling $294,183 over three years to Vasanthi Jayaraman, an associate professor in the department of biochemistry and molecular biology at the University of Texas Health Science Center in Houston.
The funds are helping support Jayaraman’s study of a type of glutamate receptor known as a calcium-permeable AMPA receptor. AMPA receptors cause toxicity and are thought to be a major trigger for selective motor neuron death and the resulting loss of muscle control in ALS.
Jayaraman and colleagues plan to develop AMPA receptor antagonists that prevent activation of the calcium-permeable AMPA receptors without causing harmful side effects or affecting the function of other subtypes of glutamate receptors.
Illuminating the role of MCT-1 in neurodegeneration
Youngjin Lee, postdoctoral associate in the department of neurology at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA development grant totaling $179,997 over three years.
The funds are helping support Lee's study of the activity, regulation and function of a type of transporter protein called MCT-1 in neurodegeneration.
Lee is testing the hypothesis that the death of motor neurons in ALS may be caused by the failure of glial cells to provide enough necessary energy components called substrates — particularly one called lactate, which is delivered by MCT-1.
Deciphering the signaling between cells that provokes disruption of mitochondrial function
MDA awarded a development grant totaling $180,000 over three years to Edward Owusu-Ansah, a postdoctoral fellow in the department of genetics at Harvard Medical School in Boston.
The funds are helping support Owusu-Ansah's research into the molecular mechanisms underlying normal and abnormal function in the cellular power factories known as mitochondria.
In a fruit fly research model, Owusu-Ansah plans to examine the intracellular signaling that contributes to disruption of mitochondrial functioning and leads to compromise of a range of biochemical and metabolic activities in cells.
Elucidating the 'good' and the 'bad' roles of CD4+ T cells in immune system dysfunction
MDA awarded a development grant totaling $180,000 over three years to Junping Xin, research associate at the Neuroscience Institute, Loyola University Medical Center in Chicago, and Edward Hines Jr. Veterans Administration Hospital in Hines, Ill.
The funds are helping support Xin’s research into the effects of immune system dysfunction, particularly with regard to the CD4+ T cells, which, when dysregulated, may cause an increase in disease-related inflammation in people with ALS.
It’s known, however, that CD4+ T cells also play an important role in supporting motor neuron survival. Xin and colleagues plan to elucidate the mechanisms of the CD4+ T cell-mediated neuroprotection as well as the effects that result when the cells become dysfunctional.
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