Nerve growth and plasticity. Formation of lasting memories, aging, disease, and treatment of spinal cord injury
Description: The common denomimator for the program is growth and loss of nerve fibers, how beneficial nerve fiber growth, such as plasticity, can be accomplished, and how degenerative processes, such as in injury and ageing, can be counteracted. We focus on the role of the Nogo signaling system for formation of lasting memories and on brain aging and its consequences for memory and disease vulnerability, using the prematurely aging mtDNA mutator mouse targeting mitochondria in all cells. We also study mice targeting mitochondria specifically in DA neurons. We will soon initiate clinical trials of Imatinib in cervical spinal cord injury. Our take on the omics options is that once an interesting observation has been made by hypothesis-driven research, in which a limited number of genes have been investigated, one applies a helicopter perspective, using "omics" to collect unbiased infor¬mation about possible alterations of any and all RNA or protein species. This provides libraries in which novel RNA or protein alterations can be identified that could not have been predicted by a focused method, but can used to build new hypotheses. The work will be carried out according to five aims: 1. To reveal roles of the inhibitory Nogo signaling group of genes for synaptic plasti¬city, formation of lasting memories and brain function. 2. To understand how aging affects brain plasticity and memory, and how aging phenotypes can be counteracted by environmental factors, using the "speed-aging" mtDNA mutator mouse. 3. To direct mitochondrial dysfunction to specific sets of neurons. 4. To determine if individual differences in learning and memory skills are reflected by alterations of Nogo signaling. 5. To run a clinical trial of Imatinib (Glivec) in acute cervical spinal cord injury.
The PI and coapplicants Anna Josephson and Tobias Karlsson will work with a team of scientists, technicians and students dedicated to the different aspects of the project. The VR grant is the backbone in our research program. It allows the group to share excellent technicians who represent methodological continuity and expertise in animal research. Gabriella Smedfors (Karolinska MD/PhD program) and three additional MD students have recently joined. The mtDNA mutator mouse is studied by postdoc Jaime Marie Ross and researcher Giuseppe Coppotelli. For STED "Nanoscopy" we collaborate with Hans Blom at the SciLife ALM facility. To target mitochondrial function in DA neurons we collaborate with Nils-Göran Larsson. Clincial trials of Imatinib will be led by neurosurgeon Mikael Svensson.
We address some of the most important outstanding issues in neuroscience, including the formation of memories that lasts for weeks and months, a less studied area. Understanding regulatory mechanisms behind structural synaptic plasticity in health, disease, and aging, should help finding targets for drugs to improve plasticity and memory. We will use unbiased transcriptomics and proteomics to identify additional mechanisms. The human population is aging, making it increasingly important to understand how aging may impair brain function. We study this in two models that test the mitochondrial hypothesis of aging in the entire body (the speed-aging mtDNA mutator mouse), and in a specific set of well understood neurons (targeting DA neurons), respectively. Emerging preliminary data indicate that both dietary supplements and exercise are able to delay aging in mutator mice, suggesting that the model has similarities to human aging. The fact that these interventions only provide limited improvements of mouse health are also in line with the human experience that the genetic background has a major impact on healthy aging. We can therefore use the mouse model to analyze how interventions improve health. The use of Imatinib to treat acute spinal cord injury will now enter its first clinical trial. Fast treatment should minimize unwanted cortical plasticity prior to recovery. Any degree of improved r
Funder: Vetenskapsrådet
Amount: SEK 4,000,000
Funding type: research
Funder scheme: Project grant
Start date: 2016-01-01
End date: 2019-12-31
Investigator: Lars Olson
Institution: Karolinska Institutet
Funded outputs count: 0
Funder award ID: 2015-02657
OpenAlex ID: G8917717151