R01GM146257

Homeostatic Reset as a New Therapeutic Paradigm for Slow Progression Diseases - Project Summary

This project responds to NIH Directors TRA RFA-RM-20-013 and will test the hypothesis that homeostatic restoration of small GTPase signaling to modify Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) pathogenesis is a game-changing therapeutic approach compared to unidirectional targeting. If proven, this new and innovative paradigm will have far-reaching and transformative impact for targeting other chronic diseases and disorders such as autism spectrum disorder, schizophrenia, and drug addiction.

The predominant and conventional therapeutic strategies in treating human diseases are unidirectionally inhibiting or stimulating affected biological processes. However, in many chronic diseases such as AD and ALS, complete inhibition or activation of the affected signaling events may themselves promote diseases. Disease progression can also be spatiotemporal, with initial activation followed by inhibition or vice versa, as well as activation versus inhibition at different brain regions. Thus, simple unidirectional targeting may itself be a major reason that no drugs have successfully prevented, reversed, or even modified the disease course for such neurodegenerative disorders.

To overcome this formidable challenge, new therapeutic paradigms must be investigated. One approach is to restore homeostatic balance instead of completely inhibiting or activating the affected signaling pathways. This approach is largely untested for AD and ALS but is broadly significant because many other complex diseases also exhibit homeostatic imbalance and spatiotemporal dysregulation of signaling pathways, making the use of inhibitors or activators ineffective if used inappropriately.

This TRA project proposes to restore the homeostatic balance of Rho and Rab family small GTPase signaling, which is spatiotemporally dysregulated in AD and ALS. The classical Rho GTPases include RhoA, Rac1, and Cdc42, in which RhoA often acts in opposition to Rac1 and Cdc42 to control protein processing and trafficking as well as synaptic remodeling. Rab GTPases additionally control ER stress and protein aggregation. Our project will apply innovative dual function small molecules to investigate this antagonism for restoring their homeostatic balance. We will determine the effects of their modulation on AD and ALS hallmark proteins and pathogenesis in mouse models.

If successful, this project will deliver novel first-in-class drug leads, and the new therapeutic paradigm will transform the entire AD and ALS drug development landscape and beyond. In summary, our proposal provides a strong rationale for the transformative impact of establishing homeostatic targeting at defective signaling processes in AD and ALS. With a multi-institution and multi-disciplinary approach, this project will lead to novel and significant insights into whether targeting homeostatic balances of defective signaling can modify AD and ALS disease course, providing a pioneering example of applying the same approach for future targeting of other chronic and slow progression diseases.

University Of South Carolina

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.310 - Trans-NIH Research Support

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Columbia, South Carolina 292083403 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 3322% from $100,000 to $3,421,894.