R35GM145279

Complexity and Evolution of Splicing-Regulatory Networks - Complexity and Evolution of Splicing-Regulatory Networks Project Summary

Alternative splicing (AS) generates multiple transcript isoforms from single genes and contributes critically to the molecular, cellular, and phenotypic complexity of mammals. This process is tightly regulated by RNA-binding proteins (RBPs) which recognize specific regulatory elements in their target transcripts.

A long-standing hypothesis from the evolutionary perspective is that changes of AS regulation due to mutations in cis-regulatory sequences provide a major driving force of speciation in mammals, including closely related species such as human and chimpanzee. Indeed, divergent AS events are pervasive in different mammalian species, as well as in human populations as evident from widespread splicing quantitative trait loci (sQTLs).

Despite remarkable progress in studies of splicing-regulatory networks over the past decade, our understanding of the splicing code remains very incomplete, leaving critical questions such as:

1) Which evolutionary splicing changes in different species or in human populations have functional implications?
2) What are the underlying mutations/genetic variations that led to the divergent splicing patterns?

Building on our previous work on splicing-regulatory networks, this research program aims to address these questions. We will develop computational methods and experimental model systems to identify AS events under adaptive selection in specific lineages and map mutations leading to changes in splicing-regulatory elements that underlie splicing divergence.

Insights learned from evolutionary changes that represent nature's experiments will be leveraged to develop a more predictive splicing code. In these studies, computational and experimental approaches, including new technology development, are closely integrated by our multidisciplinary team.

If successful, this study will provide tremendous insights into the contribution of AS evolution to potential phenotypic differences among different mammalian species, to health and disease in humans, and to fundamental understanding of RNA splicing regulation.

The Trustees Of Columbia University In The City Of New York

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.

93.859 - Biomedical Research and Research Training

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

New York, New York 100323723 United States

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Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (PAR-19-367)

Amendment Since initial award the total obligations have increased 404% from $689,596 to $3,472,662.