R01NS120331

Microglia Contribution to Disease Pathogenesis in C9ORF72 ALS/FTD - Project Abstract

The role of microglia in the C9ORF72 (C9) amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) disease spectrum remains poorly understood. Early investigations found that microglia activation was significantly higher in ALS with dementia and impaired executive function, suggesting that microglia activation correlates with FTD-like symptoms in ALS.

More recent neuropathologic examinations of microglia in FTLD patient autopsy brains with mutations in progranulin versus C9ORF72 concluded that the observed microglia dysfunction was different between the two genetically different patient subgroups, suggesting specificity of microglia dysfunction depending on the etiology of the patient population.

One interesting aspect of microglia-neuron communication is the role of microglia in the maintenance and refinement of synaptic networks through the selective pruning of synapses, which occurs predominantly during development but has been shown to also be triggered in Alzheimer's disease (AD) and related dementias, including FTD. The degree of synapse loss in AD strongly correlates with cognitive decline, even more than the amount of plaque, tangles, or neuronal loss. A recent study of ALS postmortem tissue confirmed increased synapse loss in the prefrontal cortex of patients with reported cognitive impairments.

Our laboratory has preliminary data supporting the hypothesis that there is an altered neural-immune interaction in the cortical forebrain regions of C9ORF72 patients with confirmed FTD, in which microglia and neurons modify each other's function. Using patient-derived hiPSC microglia and cortical neurons, we are able to show that C9 patient-derived hiPSC microglia mono-cultures do have intrinsic phenotypes, including altered gene profiles, phagocytic activities, and lysosomal function. Most interestingly, preliminary data suggests that C9 microglia do regulate neuronal excitability and survival of C9 iPSC neurons.

To further investigate the role and contribution of microglia in C9 cortical degeneration, we propose to thoroughly investigate the intrinsic properties of C9 hiPSC-microglia (from all patient subgroups: FTD, FTD/ALS, ALS; Aim 1). For the first time, we will then co-culture these microglia with C9 and healthy control hiPSC cortical neurons to better understand the co-regulation between these two cell types (Aim 2). Finally, in the third aim, we will study microglia activation and pathology in C9 patient postmortem autopsy tissue. This will include cell-type specific genetic profiling from existing snRNA seq datasets, immunohistochemistry of microgliosis, and multi-label immunostaining for microglial-specific candidate genes/proteins in conjunction with C9 neuronal disease pathology markers (TDP-43 and C9 DPRs) to gain novel knowledge on whether microglia are preferentially altered in close vicinity to neuronal pathologies.

Dignity Health

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Phoenix, Arizona 850134409 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 2790% from $146,327 to $4,229,195.