R01NS127186

The physical biology of neurodegeneration in sporadic amyotrophic lateral sclerosis/frontotemporal dementia - On the sporadic amyotrophic lateral sclerosis-frontotemporal dementia (SALS/FTD) clinical spectrum, the aggregation and accumulation of disease-associated proteins such as TDP-43 is a notable neuropathological hallmark, yet we know little about why this highly abnormal event might occur.

Although disruptions in multiple cellular processes have been implicated in ALS, three critical gaps in knowledge remain: 1) What triggers the aggregation of wildtype proteins in sporadic disease? Is protein aggregation sufficient to drive pathology? 2) What drives the cell-specific vulnerabilities and variable clinical manifestation from ALS to FTD? 3) How do disease-associated alterations in protein homeostasis perturb communication in the tissue microenvironment?

Given that more than 95% of ALS arises sporadically, and that the mechanisms of sporadic disease remain unknown, we will look beyond individual mutations and establish a novel conceptual framework that examines the cellular changes that occur during disease states. We posit that by focusing on why TDP-43 aggregation occurs, especially in sporadic ALS, we will gain insights into pathogenic mechanisms underlying this spectrum of disorders.

Our central hypothesis is that there are physical changes at the cell and tissue scale that initiate ALS/FTD. We propose that altered biophysical properties within cells (predominantly altered molecular crowding), which are linked to mechanical perturbations to the tissue microenvironment (stiffening, inflammation, edema causing osmotic stress), lead to age-dependent cellular dysfunction by altering the dynamics of assembly, disassembly, and transport of macromolecular protein machines.

We will test this hypothesis in cellular models, animal models, and patient tissue by:
1) Using novel tools to probe the intracellular biophysical environment of cells;
2) Integrating these findings using novel genomics technologies applied to mouse models to study (i) how intracellular changes in crowding and extracellular changes in the tissue microenvironment may drive pathogenesis in vivo, and (ii) how such perturbations disrupt cell-cell communication in vulnerable regions of tissue; and
3) Relating our findings to human disease by re-examining these findings in the context of a clinically and neuropathologically deeply curated cohort of ALS/FTD patients.

These studies will allow us to address the following questions:
1) Why does abnormal protein aggregation and accumulation occur in sporadic disease, and how might this contribute to disease pathogenesis?
2) Do these alterations in protein homeostasis perturb intercellular communication in the tissue microenvironment?
3) What drives the cell type vulnerability that makes ALS/FTD unique?

The proposed work will accomplish the following:
A) Represent the first detailed survey of molecular crowding in neural cells;
B) Uncover whether a causal link between intracellular crowding, protein aggregation, and neurodegeneration exists;
C) Establish whether the impacts of intracellular crowding show cell type-specific signatures, including changes in protein-protein interactions; and
D) Provide a new framework to explore therapeutic strategies for treating ALS/FTD.

The Trustees Of Columbia University In The City Of New York

(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]

New York, New York 100323725 United States

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NIH Directors Transformative Research Awards (R01 Clinical Trial Optional) (RFA-RM-20-013)

Amendment Since initial award the total obligations have increased 388% from $1,687,039 to $8,227,499.