RF1AG094856

INHIBITION OF ABETA42 AGGREGATION BY HELIX STABILIZING PEPTIDOMIMETIC BIOMATERIALS - ALZHEIMER’S DISEASE (AD) IS THE MOST DEVASTATING DEMENTIA OF GLOBAL CONCERN. ALTHOUGH THE MECHANISM OF AD PATHOGENESIS IS STILL UNDER DEBATE, IT IS AGREED THAT AΒ AGGREGATION ARE PROMINENT HALLMARKS AND THE MAJOR RISK OF AD DUE TO THEIR TOXICITY TO NEURONS. THEREFORE, AΒ AGGREGATES, PARTICULARLY OLIGOMERS, ARE THE POTENTIAL TARGETS FOR THE INTERVENTION OF AD, AS TARGETING AND REMOVAL OF AΒ FIBRILS OR PLAQUES IS EXPECTED TO ELIMINATE THE NEURONAL TOXICITY OF AΒ AGGREGATES. HOWEVER, ERADICATION OF TOTAL AΒ PEPTIDES BY THERAPEUTIC ANTIBODIES COULD LEAD TO SEVERE SIDE EFFECTS, WHEREAS ANTI-AΒ AGGREGATION BY Β-SHEET MIMETICS COULD ONLY PREVENT OR DELAY THE PROCESS OF AGGREGATION PROCESS AND COULD NOT DISRUPT THE FORMED/EXISTING AΒ AGGREGATION. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE MOLECULAR PROBES THAT NOT ONLY PREVENT BUT ALSO DISRUPT AΒ FIBRIL FORMATION IS STILL IN AN URGENT NEED. IN CONTRAST TO Β-SHEET MIMETICS TO BLOCK AΒ FIBRILLAR GROWTH, RECENTLY WE DESIGNED A CLASS OF PEPTIDE HYBRID BIOMATERIALS THAT CAN SPECIFICALLY INTERACT AND STABILIZE AΒ HELICAL CONFORMATION, THEREBY SHIFTING THE EQUILIBRIUM OF AΒ AGGREGATION INTO OFF-PATHWAY MONOMERIC STRUCTURE, LEADING TO BOTH PREVENTION AND DISRUPTION OF AΒ AGGREGATION. THE LEAD COMPOUND COULD COMPLETELY RESTORE CELL VIABILITY AND BOOST THE LEVELS OF NEURONAL PSD-95 AND SYNAPTOPHYSIN REDUCED BY AΒ42 IN PRIMARY NEURONS, AND VASTLY PREVENT MEMORY IMPAIRMENT IN 5XFAD AD TRANSGENIC MICE. MOREOVER, THE LEAD COMPOUND COULD SIGNIFICANTLY MITIGATE MITOCHONDRIAL AND CELL STRESS, AND REMARKABLY ALLEVIATE THE SYSTEMIC INFLAMMATION INDUCED BY AMYLOID PATHOLOGY IN THE MICE. AS SUCH, OUR LONG- TERM GOAL IS TO DEVELOP NOVEL BIOMATERIALS THAT CAN PREVENT, HALT AND CURE AD. THE OBJECTIVE OF THIS PROPOSAL, THE FIRST STEP TO ACHIEVE THE LONG-TERM GOAL, IS TO ADVANCE OUR PRELIMINARY WORK BY RATIONALLY DESIGNING STRUCTURALLY RELATED ANALOGUES OF THE CURRENT LEAD, SO AS TO IDENTIFY AND DEVELOP MORE POTENT AND EFFECTIVE PEPTIDOMIMETICS THAT CAN PREVENT AND DISRUPT AΒ AGGREGATION BOTH IN VITRO AND IN VIVO BY HELICAL AΒ42 BINDING AND STABILIZATION. WE WILL FIRST DESIGN HELICAL PEPTIDIC FOLDAMER BEARING DIVERSE FUNCTIONAL GROUPS AND CLOSELY MIMIC THE BINDING PATTERN OF OUR LEAD COMPOUND. THEN WE WILL USE OUR ESTABLISHED IN VITRO ASSAYS SUCH AS 2D-NMR, EMS-IMS, CD, TEM, AND OTHER KINETIC BINDING ASSAYS TO IDENTIFY AND OPTIMIZE OUR DESIGNED COMPOUNDS THAT TARGET AND INHIBIT THE AGGREGATION OF AΒ PEPTIDES. THE COMPOUNDS WITH ACTIVITY EQUIVALENT OR BETTER THAN THE LEAD COMPOUND WILL BE USED TO STUDY THEIR ABILITY TO INHIBIT AΒ PATHOLOGY BOTH IN VITRO AND IN VIVO. THE PROPOSED STUDY IS SIGNIFICANT BECAUSE THERE IS NO EFFECTIVE STRATEGY FOR AD DIAGNOSIS AND PREVENTION. OUR RESEARCH WILL PROVIDE MOLECULES WITH NOVEL MECHANISM TO UNRAVEL AD PATHOGENIES AND TO DEVELOP POTENTIAL MOLECULAR PROBES AND THERAPEUTIC AGENTS FOR CURE OF AD. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE WE NOT ONLY PROVIDE A NEW STRATEGY FOR THE DEVELOPMENT OF NOVEL CLASS OF PEPTIDOMIMETICS THAT PREVENT AND DISRUPT AΒ AGGREGATION, IN ADDITION, THIS APPROACH OF RATIONAL DESIGN FOR THE RECOGNITION OF AΒ SURFACE CAN BE EASILY EXTENDED TO IDENTIFY NEW MATERIALS TARGETING OTHER AMYLOID DISEASES SUCH AS HUNTINGTON’S DISEASE AND DIABETES DISEASES.

University Of South Florida

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE 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. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH 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 on Aging (NIA) [HHS - NIH]

Tampa, Florida 33612 United States

Single Zip Code

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