Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people in the world, but there is no effective therapy. Understanding molecular events leading to AD is vital for the development of new treatments. Our goal is to study the role of death-associated protein kinase 1 (DAPK1) in AD using mouse models and to determine whether DAPK1 is important for neuronal cell death and the development of Alzheimer’s disease. This study could have a significant impact on our basic understanding of AD, and might eventually lead to AD.
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- Tae Ho Lee, PhDBeth Israel Deaconess Medical Center, Harvard Medical School (Boston, MA)ID:A2017180SCollaborators:Bradley T. Hyman, MD, PhDJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$300,000
- Chaeyoung Kim, PhDGladstone Institutes (San Francisco, CA)
Apolipoprotein E (apoE) has important roles in both normal central nervous system physiology and neuropathology, such as Alzheimer’s disease (AD). Importantly, the apoE4, one of apoE isoforms, is the major genetic risk factor for AD, and generates toxic fragments that cause mitochondrial dysfunction and drive neurodegeneration. Because mitochondrial dysfunction and metabolic impairment are critical elements of AD pathology, I will study how apoE4 and its neurotoxic fragments interact with mitochondria and alter mitochondrial activity. This largely unexplored approach will provide insight into the mechanisms underlying the role of apoE4 in AD and may identify new therapeutic targets to treat apoE4-associated AD.ID:A2017214FMentors:Robert W. Mahley, MD, PhDJuly 1, 2017 to June 30, 2019Alzheimer's DiseasePostdoctoral Fellowship$100,000
- Trevor McGill, PhDOregon Health and Science University (Portland, OR)
Age-related macular degeneration (AMD) is the most common cause of legal blindness in the elderly in developed countries, and is a leading cause of blindness worldwide. The typical American diet is low in nutritional factors that may reduce the risk or severity of AMD. The goal of this project is to determine whether being deprived of these nutrients has consequences for the development of AMD, and to determine the mechanisms by which this occurs. Results from these studies will provide direct evidence for the importance of these nutritional factors in maintaining retinal health and preventing advanced retinal disease, and may reveal new options for therapeutic intervention.ID:M2017073Collaborators:Paul S. Bernstein, MD, PhD; Martha Neuringer, PhDJuly 1, 2017 to June 30, 2019Macular DegenerationStandard$160,000
Recipient of The Carolyn K. McGillvray Award for Macular Degeneration Research
- Krishnakumar Kizhatil, PhDThe Jackson Laboratory (Bar Harbor, ME)
Glaucoma is a devastating neurodegenerative disease that causes blindness. Glaucoma results from increased pressure in the eye; however, the mechanistic basis of the pressure increase is largely undetermined. Neurons innervating the eye play a role in controlling pressure, but again the specific mechanisms are not clear. We will determine the mechanistic basis of neuronal control of eye pressure using mice and modern imaging and molecular methods.ID:G2017152Collaborators:Simon W. M. John, PhDJuly 1, 2017 to June 30, 2019GlaucomaStandard$150,000
- Daniel Bos, PhDErasmus Medical Center (Rotterdam, Netherlands)
Atherosclerosis, or hardening of the arteries, is increasingly recognized as an important risk factor for dementia. Yet, it remains unclear whether the progression of atherosclerosis at different locations in the arterial system also contributes to changes in the structure or function of the brain, and ultimately to dementia. Knowledge of the dynamics of atherosclerosis and its role in brain changes will greatly improve our insight into the development of dementia. At a later point, this knowledge may even offer therapeutic or preventive opportunities to reduce the number of persons suffering from dementia by targeting atherosclerosis.ID:A2017424FCollaborators:M. Arfan Ikram, MD, PhDMentors:Meike Vernooj, MD, PhDJuly 1, 2017 to June 30, 2019Alzheimer's DiseasePostdoctoral Fellowship$98,823
- Yan Chen, PhDThe University of Texas Medical Branch at Galveston (Galveston, TX)
Every morning when we open our eyes to see the world around us, the neurons in our retina begin to work. Their intense work load demands high energy. The retinal neurons rely on their supporting cells, such as retinal pigment epithelium (RPE) cells, to provide them with the fuel to meet their energy needs. In this project, we will study the mechanisms of energy production and regulation, in both healthy and diseased eyes, particularly those with AMD.ID:M2017186Co-principal Investigators:Dean Jones, PhDJuly 1, 2017 to June 30, 2019Macular DegenerationStandard$160,000
- Derek Welsbie, MD, PhDUniversity of California, San Diego (La Jolla, CA)
Nerve cells called retinal ganglion cells (RGCs) form the connection between the eye and the brain. In glaucoma, these nerve cells die and vision is permanently lost. We have previously shown that a protein called dual leucine zipper kinase (DLK) is critical for the death of these cells. Thus, this proposal seeks to develop a gene therapy vector that might interfere with DLK and prevent RGC death and accompanying vision loss.ID:G2017212Collaborators:Donald J. Zack, MD, PhDJuly 1, 2017 to June 30, 2019GlaucomaStandard$150,000
Recipient of the Dr. Douglas H. Johnson Award
- Philippe Mourrain, PhDStanford University (Stanford, CA)
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world but its genetics is still unclear. Most of the DNA variations in AMD patients are found outside of the genes, and it is extremely hard to know whether these variants are actual mutations and what genes they affect. We have found that some of these variants are located in genome regions conserved down to the zebrafish, and surrounded by the same neighborhood of genes as in the human genome. Their preservation in the zebrafish allows us to visualize in this transparent genetic vertebrate model whether these variants are just neutral or if they disrupt the regulation of one the neighbor genes, possibly revealing the actual gene affected in AMD human patients.ID:M2017209Co-principal Investigators:Romain Madelaine, PhDCollaborators:Jeffrey Goldberg, MD, PhD; Douglas Vollrath, MD, PhDJuly 1, 2017 to June 30, 2019Macular DegenerationStandard$160,000
This grant is made possible by support from the Nancy Ferguson Seeley Trust in memory of Mildred F. Ferguson.
- Shahrnaz Kemal, PhDNorthwestern University (Evanstown, IL)
Alzheimer's disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. It is critical that we find new therapies to prevent and treat AD. The experiments in this proposal are designed to find new pathways by which toxic forms of beta amyloid (Aβ), a peptide associated with AD, damages microtubules, tube-like structures used to move components around in cells, including neurons in the brain. Typically, damage to microtubules is blamed on abnormal tau formations in the Alzheimer’s brain, but we plan to test the novel hypothesis that Aβ has neurodegenerative effects independent of tau that affect microtubule stability, and that microtubule stabilizing agents can protect neurons against Aβ neurotoxicity. New drugs will be tested to determine if they can reverse some of the detrimental effects of Aβ accumulation in the brain.ID:A2017033FMentors:Robert Vassar, PhDJuly 1, 2017 to June 30, 2019Alzheimer's DiseasePostdoctoral Fellowship$100,000
- Sarah DeVos, PhDMassachusetts General Hospital/Harvard University (Boston, MA)
A major driver of Alzheimer’s disease (AD) is the accumulation of the protein tau that travels through the human brain in a constant pattern. Tau molecules become misshapen and aggregate in AD, though no one has yet identified how, or even if, these tau accumulations result in neuronal death. In this research, we have developed a fluorescent tool that will allow us to watch tau collect in neurons both in cell culture as well as the living adult mouse brain. Using this tool, this research aims to observe directly, in real time, what happens once a neuron develops a tau aggregate, as well as to study which genes increase or decrease in a neuron once it develops one of these tau accumulations. Together, these data will help us better understand the immediate changes that occur in adult neurons when they develop AD-like tau accumulations and may help identify new druggable pathways involved in the development of AD in human patients.
Note: This grant was terminated by the investigator in February of 2018 when she left Harvard University for an industry position.ID:A2017436FMentors:Bradley Hyman, MD, PhDJuly 1, 2017 to June 30, 2019Alzheimer's DiseasePostdoctoral Fellowship$100,000