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RF1NS143938

Project Grant

Overview

Grant Description
SPATIAL ORGANIZATION AND CONFORMATIONAL ENSEMBLES OF AMYLOIDS INSIDE CELLS - PROJECT SUMMARY THE FORMATION OF INTRACELLULAR INCLUSIONS CONTAINING FIBRILLAR AGGREGATES OF ALPHA-SYNUCLEIN (Α-SYN) IS A HALLMARK OF NEURODEGENERATIVE DISEASES SUCH AS LEWY BODY DEMENTIA, PARKINSON’S DISEASE, AND MULTIPLE SYSTEMS ATROPHY. AN INTRINSICALLY DISORDERED MONOMER, Α-SYN, CAN ASSEMBLE INTO VARIOUS FIBRILLAR FORMS INFLUENCED BY ITS ENVIRONMENT. UNDERSTANDING THE CONFORMATIONS THAT Α-SYN ADOPTS IN HEALTH AND DISEASE IS CRUCIAL FOR DEVELOPING DIAGNOSTIC AND THERAPEUTIC TOOLS. ALTHOUGH ADVANCES IN STRUCTURAL BIOLOGY HAVE ACCELERATED THE CHARACTERIZATION OF ISOLATED AMYLOID FIBRILS, IT IS ESSENTIAL TO KNOW THE Α-SYN STRUCTURES IN BIOLOGICAL SETTINGS, AS ISOLATED FIBRILS MAY NOT REPRESENT IN VIVO CONFORMATIONS. CURRENT METHODS, SUCH AS ISOLATING FIBRILS FROM POST-MORTEM TISSUES OR USING SEEDING TO AMPLIFY FIBRILS IN VITRO, MIGHT NOT CAPTURE THE PREVALENT IN-CELL CONFORMATIONS. THIS PROJECT AIMS TO IDENTIFY THE AMYLOID CONFORMATIONS AND THEIR ABUNDANCES INSIDE CELLS, WHICH WILL ENHANCE OUR UNDERSTANDING OF AMYLOID PROPAGATION AND AID IN IDENTIFYING BIOLOGICALLY RELEVANT STRUCTURES. WE WILL INVESTIGATE HOW DIFFERENT CELLULAR ENVIRONMENTS AFFECT SEEDED AMYLOID PROPAGATION BY USING BIOSENSOR CELL LINES AND NEURONS. IN BIOSENSOR CELL LINES EXPRESSING WILD-TYPE AND MUTANT Α-SYN, WE WILL INTRODUCE Α-SYN AND ASSESS ITS AGGREGATION INTO AMYLOID FIBRILS UPON EXPOSURE TO SEEDS. THIS APPROACH WILL ALLOW US TO COMPARE AMYLOID PROPAGATION IN VITRO WITH THAT INSIDE CELLS. IN NEURONS, WE WILL STUDY THE SEEDED AMYLOID PROPAGATION OF WELL-CHARACTERIZED Α-SYN FIBRILS, CONSIDERING THE INFLUENCE OF THE CELLULAR ENVIRONMENT ON FIBRIL FORMATION AND PROPAGATION. UNDERSTANDING HOW SPECIFIC CELL TYPES AFFECT AMYLOID PROPAGATION IS CRUCIAL, AS DIFFERENT NEURODEGENERATIVE DISEASES INVOLVE AMYLOID FIBRILS ACCUMULATING IN DISTINCT CELL TYPES. ADDITIONALLY, WE WILL ANALYZE AMYLOID STRUCTURES FROM TISSUE SEEDED LEWY BODY DEMENTIA PATIENTS. BY COMPARING THESE STRUCTURES WITH KNOWN Α-SYN FIBRIL CONFORMATIONS, WE AIM TO IDENTIFY UNIQUE FEATURES AND POLYMORPHS RELEVANT TO DISEASE PATHOLOGY. WE WILL USE A MULTI-SCALE APPROACH WITH TWO COMPLEMENTARY, STATE-OF-THE-ART IN SITU STRUCTURAL TECHNIQUES: IN-CELL DNP SENSITIVITY-ENHANCED NMR SPECTROSCOPY AND CELLULAR CRYO- ET/SUBTOMOGRAM AVERAGING TO CHARACTERIZE THE CONFORMATIONAL ENSEMBLES AND SPATIAL ORGANIZATION OF Α-SYN AMYLOIDS IN SITU. THIS COMPREHENSIVE APPROACH WILL PROVIDE INSIGHTS INTO THE STRUCTURAL DIVERSITY, MOLECULAR INTERACTIONS AND ORGANIZATION OF Α-SYN AMYLOIDS, AS WELL AS THEIR EFFECTS ON CELLS, ULTIMATELY ADVANCING OUR UNDERSTANDING OF NEURODEGENERATIVE DISEASE MECHANISMS AND PATHOLOGY, AND INFORMING THE DEVELOPMENT OF TARGETED DIAGNOSTICS AND THERAPEUTICS.
Funding Goals
(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.
Grant Program (CFDA)
Place of Performance
Texas United States
Geographic Scope
State-Wide
The University Of Texas Southwestern Medical Center was awarded Cellular Amyloid Conformations: Insights for Neurodegenerative Disease Project Grant RF1NS143938 worth $3,178,675 from National Institute on Aging in August 2025 with work to be completed primarily in Texas United States. The grant has a duration of 4 years and was awarded through assistance program 93.866 Aging Research. The Project Grant was awarded through grant opportunity Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings (R01 - Clinical Trial Not Allowed).

Status
(Ongoing)

Last Modified 8/20/25

Period of Performance
8/13/25
Start Date
7/31/29
End Date
1.0% Complete

Funding Split
$3.2M
Federal Obligation
$0.0
Non-Federal Obligation
$3.2M
Total Obligated
100.0% Federal Funding
0.0% Non-Federal Funding

Activity Timeline

Interactive chart of timeline of amendments to RF1NS143938

Additional Detail

Award ID FAIN
RF1NS143938
SAI Number
RF1NS143938-1021727309
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Funding Office
75NN00 NIH National Insitute on Aging
Awardee UEI
YZJ6DKPM4W63
Awardee CAGE
1CNP4
Performance District
TX-90
Senators
John Cornyn
Ted Cruz
Modified: 8/20/25