U54NS123985

Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal Proteases - Project Summary

Pathological tau deposition occurs in a subset of neurodegenerative disorders, including frontotemporal lobar degeneration with tau inclusions (FTLD-TAU). Much of what is known about FTLD-TAU is derived from mutant tau models or overexpression. However, a unified view of overall tau metabolism—from its initial production, interactions with molecular chaperones, post-translational modifications, targeting to lysosomes/autophagy, and resultant degradation—has not been generated.

The long-term goal of this proposed FTD Center Without Walls (CWOW) is to improve our understanding of the pathobiological mechanisms underlying FTD-TAU. Its overall objective is to elucidate the genes, molecules, and pathways that regulate tau metabolism and to determine the impact of disease-associated mutations and variants. Our central hypothesis is that proper tau metabolism requires the precise, coordinated action of molecular chaperones, co-chaperones, PTMs, and degradation machinery that each represent regulatory nodes. Genetic mutations in tau and other pathway members can disrupt tau metabolism, leading to tau accumulation, secretion, and neurodegeneration.

The center will be led by Dr. Aimee Kao, who will also lead Core A: Administration and Data Core (with co-lead Dr. Yokoyama) and Project 1: Tau Molecular Chaperones, Targeting, and Proteolysis (with co-I Dr. Agard). Dr. David Agard will oversee Core B: Macromolecular and Cellular Structure Core. Dr. Jennifer Yokoyama will lead Core C: Genomics and Transcriptomics. Finally, Dr. Celeste Karch will lead Project 2: Tau Half-Life and Secretion.

We will achieve these objectives through four specific aims:

Aim 1: Understand the normal process of tau metabolism as a series of decisions that are made at regulatory nodes.
Aim 2: Identify and test the functional relevance of genetic variants in MAPT and other tau metabolism genes, in in vitro, cell, and ineuron models, on each of the tau metabolism regulatory nodes.
Aim 3: Integrate findings from projects and cores to produce a Tau Metabolism and Variant Database (TMVDB), which will serve as a reference point for the field.
Aim 4: Integrate findings from projects and cores to produce a Tau Polygenic Risk Score (TPRS), which will stratify genetic risk for tauopathy.

Upon successful completion of these aims, the proposed FTD CWOW will have provided fundamental information about tau metabolism, defined mechanistic nodes predisposing to tauopathy, and generated the TMVDB and TPRS, new resources for the fields of tauopathy and neurodegeneration research. It will generate critically important information about tau homeostasis and a foundational basis from which to build and frame subsequent investigations into tau pathobiology and toxicity.

San Francisco Regents Of The University Of California

(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.

93.866 - Aging Research

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

National Institute on Aging (NIA) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

Center without Walls for Molecular Mechanisms of Neurodegeneration in Frontotemporal Degeneration (FTD) (U54 Clinical Trial not Allowed) (RFA-NS-21-003)

Amendment Since initial award the total obligations have increased 399% from $1,808,602 to $9,032,267.