Dena Bou Dubal
University Of California San Francisco
Project start date: 2009-09-01
Project end date: 2014-08-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Dena Bou Dubal
COLLAGEN VI: NOVEL MECHANISMS AND FUNCTIONS IN ALZHEIMER´S DISEASE
Dena Bou Dubal
J. David Gladstone Institutes, San Francisco, Ca 94158
Grant 5K08AG034531-02 from National Institute On Aging
Abstract: With the rapid increase in the world´s aging population, a cure for neurodegenerative conditions is urgently needed. Alzheimer´s disease (AD), the most common disease of memory in the elderly, devastates the minds of millions of people every year. Research over the past decade has revealed that amyloid-¿ (A¿) peptides, soluble toxins, play a central role in the pathogenesis of AD. However, despite our growing knowledge of how AD devastates the brain, there are no effective treatments to prevent or modify the course of the disease. This proposal is aimed at identifying and developing neuroprotective strategies against AD. We propose to investigate novel functions of collagen VI, an extracellular matrix protein, in protection against the deleterious effects of A¿ in the brain. Our preliminary studies show that collagen VI, which is robustly increased in the brain in a mouse model of AD and in human AD, dramatically prevents the toxicity of A¿ in mouse neurons. To extend these findings, in Specific Aim 1, we will examine the extracellular actions of collagen VI, with the goal of determining whether collagen VI binds A¿, alters its assembly, and enhances amyloid plaque formation. In Specific Aim 2, we will investigate intracellular mechanisms of collagen VI- mediated protection to determine whether collagen VI alters the expression of key survival factors to counter A¿ toxicity. In Specific Aim 3, we will focus on the effects of collagen VI on behavior and ascertain whether collagen VI prevents A¿-dependent cognitive dysfunction. Our studies may reveal key protective mechanisms that could serve as direct targets for the development of treatments for AD and other diseases of aging. The candidate is a physician-scientist with a strong commitment to a career in academic medicine focused on identifying strategies to protect against neurodegenerative conditions of aging, such as Alzheimer´s disease and related dementias. The candidate has a PhD in neuroscience and an MD with clinical training in neurology and subspecialty training in dementias. The research proposal and career development plan build upon her training in neuroscience, aging, and neurodegenerative conditions to provide expertise in transgenic mouse models of Alzheimer´s disease, behavioral analysis, histology, cell culture and viral vectors. The mentoring and research experience described in the proposal would provide resources, salary. RELEVANCE Although Alzheimer´s disease (AD) devastates the minds of millions of people, there are no truly effective treatments. This proposal is aimed at developing strategies to protect the brain against AD by investigating newfound protective actions of collagen VI, a protein whose effects in the brain are virtually unknown. The mechanisms of this protection may be direct targets for developing effective AD treatments
Keywords: AD model; Address; Age; Aged 65 and Over; Aging; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimer`s disease model; Alzheimers Dementia; Alzheimers disease; Amentia; Amyloid; Amyloid A4 Protein Precursor; Amyloid Plaques; Amyloid Protein Precursor; Amyloid Substance; Amyloid beta-Protein Precursor; Animal Model; Animal Models and Related Studies; Assay; Atomic Force Microscope; Atomic Force Microscopy; Autopsy; Behavior; Behavioral; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological Assay; Blotting, Western; Brain; Cell Communication and Signaling; Cell Culture Techniques; Cell Death; Cell Signaling; Cell Survival; Cell Viability; Cell-Extracellular Matrix; Cell/Tissue, Immunohistochemistry; Cells; Cessation of life; Clinical; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive deficits; Cognitive function abnormal; Collagen; Data; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dentate Fascia; Dentate Gyrus; Development; Development Plans; Disease; Disorder; Disturbance in cognition; Doctor of Philosophy; Dysfunction; ECM; ELISA; Elderly; Elderly, over 65; Employee Strikes; Encephalon; Encephalons; Environment; Enzyme-Linked Immunosorbent Assay; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Matrix, Integrins; Extracellular Signal-Regulated Kinase Gene; Extracellular Space; Family; Fascia Dentata; Fellowship; Force Microscopy; Functional disorder; Generations; Genes; Goals; Gyrus Dentatus; Histology; Human; Human, General; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; Impaired cognition; Infrastructure; Integrin Binding; Integrins; Intercellular Space; Intracellular Communication and Signaling; Investigators; Knowledge; Laboratories; Learning; Lentiviral Vector; Lentivirus Vector; MAP Kinase Gene; MAPK; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Measures; Mediating; Medicine; Memory; Mentors; Methods; Methods and Techniques; Methods, Other; Mice; Microscopy, Atomic Force; Mind; Mitogen-Activated Protein Kinase Gene; Modeling; Molecular; Molecular Interaction; Molecular Target; Murine; Mus; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous System, Brain; Neural Cell; Neuritic Plaques; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurology; Neuron Degeneration; Neurons; Neurosciences; Organ; Pathogenesis; Pathway interactions; Peptides; Peripheral; Ph.D.; PhD; Physicians; Physiopathology; Play; Primary Senile Degenerative Dementia; Principal Investigator; Programs (PT); Programs [Publication Type]; Protein Binding; Proteins; RT-PCR; RTPCR; Receptor Protein; Receptor Signaling; Research; Research Infrastructure; Research Personnel; Research Proposals; Research Resources; Researchers; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Rodentia; Rodentias; Role; Salaries; Scanning Force Microscopy; Science of Medicine; Scientist; Senescence; Senile Plaques; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Staining method; Stainings; Stains; Strikes; Strikes, Employee; Structure of dentate gyrus; Techniques; Testing; Toxic effect; Toxicities; Toxin; Training; Transgenic Mice; Viral Vector; Wages; Western Blotting; Western Blottings; Western Immunoblotting; advanced age; aging population; amyloid beta plaque; amyloid precursor protein; amyloid-b plaque; biological signal transduction; career; career development; cognitive dysfunction; cognitive loss; cognitively impaired; cored plaque; cytotoxic; dementia of the Alzheimer type; density; dentate gyrus; design; designing; diffuse plaque; disease/disorder; effective therapy; elders; experience; experiment; experimental research; experimental study; extracellular; familial Alzheimer disease; familial Alzheimer disease (FAD); gene product; geriatric; in vivo; intervention development; late life; later life; model organism; molecular marker; mouse model; mutant; necrocytosis; necropsy; neural degeneration; neurodegeneration; neurodegenerative illness; neuronal; neuronal degeneration; neuropathology; neuroprotection; novel; older adult; older person; pathophysiology; pathway; postmortem; prevent; preventing; primary degenerative dementia; programs; protein blotting; receptor; research study; response; reverse transcriptase PCR; senescent; senile dementia of the Alzheimer type; senior citizen; shRNA; short hairpin RNA; skills; small hairpin RNA; social role; therapy development; treatment development
Project start date: 2009-09-01
Project end date: 2014-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-AG-09-012
5K08AG034531-02 (2010): $108000
1K08AG034531-01 (2009): $108000