RF1NS140600

INVESTIGATING ABERRANT VESICULAR DEGRADATION AND LIPID METABOLISM IN NEURODEGENERATION - BOSCO/MASSI – ABSTRACT PROFILIN-1 (PFN1) IS AN ACTIN-BINDING PROTEIN THAT IS BEST KNOWN FOR ITS ROLE IN REGULATING CYTOSKELETAL DYNAMICS. IN 2012, WE IDENTIFIED MUTATIONS IN PFN1 THAT CAUSE THE UNIFORMLY LETHAL NEURODEGENERATIVE DISEASE AMYOTROPHIC LATERAL SCLEROSIS (ALS), HOWEVER, THE MECHANISM UNDERLYING PFN1-MEDIATED ALS REMAINS POORLY UNDERSTOOD. TO ADDRESS THIS KNOWLEDGE GAP, OUR TEAM HAS ESTABLISHED AND/OR CHARACTERIZED MULTIPLE ALS-PFN1 MODELS, INCLUDING HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) AND KNOCK-IN MICE WITH AN ALS-LINKED PFN1 MUTATION, BOTH OF WHICH ALLOW FOR INVESTIGATION OF ALS-LINKED PFN1 AT PHYSIOLOGICAL EXPRESSION LEVELS. FURTHER, WE HAVE ESTABLISHED METHODS FOR ISOLATING RECOMBINANT PFN1 VARIANTS FOR STRUCTURAL STUDIES USING NMR AND FOR EXAMINING THE MOLECULAR DYNAMICS OF PFN1 IN COMPLEX WITH RELEVANT BINDING PARTNERS. THROUGH OUR COLLABORATIVE RESEARCH, THE BOSCO AND MASSI LABORATORIES UNCOVERED DEFECTS IN PHAGOCYTIC VESICULAR DEGRADATION IN IPSC-DERIVED MICROGLIA CELLS. THE PHAGOCYTOSIS, AUTOPHAGY AND ENDOLYSOSOMAL PATHWAYS ALL ENTAIL VESICULAR DEGRADATION WITH A CONVERGENCE ON THE LYSOSOME. NOTABLY, OUR STUDY IDENTIFIED A NOVEL INTERACTION BETWEEN PFN1 AND PHOSPHATIDYLINOSITOL 3-PHOSPHATE (PI3P), A LIPID THAT IS ESSENTIAL FOR AUTOPHAGY AND THAT IS INVOLVED THROUGHOUT THE VESICULAR DEGRADATION PATHWAY. BASED ON THESE OBSERVATIONS, WE HYPOTHESIZE THAT MUTANT PFN1 IMPAIRS AUTOPHAGY AND VESICULAR DEGRADATION THROUGH A GAIN-OF-TOXIC INTERACTION WITH PI3P AND POTENTIALLY OTHER PIPS INVOLVED IN VESICULAR DEGRADATION. THE GOALS OF THIS PROPOSAL ARE TO INTERROGATE THIS HYPOTHESIS USING PIP-SPECIFIC PROBES AND MODULATORS IN MULTIPLE ALS-RELEVANT CELL TYPES (AIM 1) AND THROUGH BIOPHYSICAL BINDING AND STRUCTURAL ANALYSES OF PIP/PFN1 COMPLEXES WITHIN BIOLOGICALLY RELEVANT MEMBRANE CONTEXTS (AIM 2). OUR PRELIMINARY LIPIDOMICS DATA ALSO REVEALED LIPID DYSREGULATION IN ALS-PFN1 MICE THAT MAY BE RELEVANT TO DISEASE PATHOGENESIS. INTRIGUINGLY, SEVERAL OF THESE LIPIDS ALSO REGULATE AUTOPHAGY. IN AIM 3, WE WILL EXAMINE POTENTIAL LINKS BETWEEN AUTOPHAGY IMPAIRMENT AND SPECIFIC CLASSES OF LIPIDS IN MODELS OF ALS-PFN1 AND TDP-43 THAT ARE ASSOCIATED WITH BOTH ALS AND THE RELATED DISORDER FRONTOTEMPORAL DEMENTIA (FTD). COLLECTIVELY, THE OUTCOMES FROM THESE AIMS WILL PROVIDE NOVEL INSIGHT INTO PFN1-MEDIATED ALS AND UNPRECEDENTED STRUCTURAL INFORMATION ON PFN1/PIP COMPLEXES. WE WILL ALSO GAIN BROAD INSIGHT INTO MECHANISMS OF LIPID DYSHOMEOSTASIS AND THEIR LINK TO VESICULAR DEGRADATION IN ALS AND ALS/FTD, WITH THE GOAL OF IDENTIFYING INTERVENTIVE STRATEGIES THAT WILL MITIGATE LIPID DYSHOMEOSTASIS IN THESE DISORDERS.

University Of Massachusetts Medical School

(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]

Worcester, Massachusetts 01655 United States

Single Zip Code

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