A synthetic biology platform to identify novel anti-aging natural products

Information

  • Research Project
  • 8714151
  • ApplicationId
    8714151
  • Core Project Number
    R43AG045956
  • Full Project Number
    1R43AG045956-01A1
  • Serial Number
    045956
  • FOA Number
    PA-13-234
  • Sub Project Id
  • Project Start Date
    6/15/2014 - 10 years ago
  • Project End Date
    11/30/2014 - 10 years ago
  • Program Officer Name
    MURTHY, MAHADEV
  • Budget Start Date
    6/15/2014 - 10 years ago
  • Budget End Date
    11/30/2014 - 10 years ago
  • Fiscal Year
    2014
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    6/11/2014 - 10 years ago
Organizations

A synthetic biology platform to identify novel anti-aging natural products

DESCRIPTION (provided by applicant): The ultimate goal of research into the biology of aging is to identify pharmaceutical interventions to increase both lifespan and healthspan of humans. The natural product rapamycin has been shown to significantly extend the lifespans of all model organisms tested including fungi, flies, worms, and mice. However, chronic treatment with rapamycin also causes unwanted side effects including moderate immunosuppression and impaired glucose tolerance and insulin function. Recent research suggests that rapamycin functions by binding and blocking signaling from two independent signaling complexes, mTORC1 and mTORC2. It has been shown that the beneficial effects on lifespan are due to the downregulation of mTORC1 signaling upon binding by rapamycin. On the other hand, the deleterious side effects of rapamycin result from the downregulation of mTORC2 signaling upon rapamycin binding. Thus, an ideal anti-aging pharmaceutical agent would be highly similar to rapamycin, but have high specificity for mTORC1 and little specificity for mTORC2. Radiant Genomics believes that the enormous diversity of natural product gene clusters that can be identified through a combination of bioinformatics and next generation sequencing of metagenomes and individual organisms can now be mined to provide candidate natural rapamycin analogs that may have desired binding properties, bypassing hurdles blocking traditional methods of natural product discovery. To do this, we have developed a synthetic biology platform that has three main pipelines: 1) a method to bioinformatically identify gene clusters that code for natural rapamycin analogs, 2) a method to clone and manipulate these gene clusters into constructs for transformation into a heterologous host, 3) a method to transform these clusters into an engineered host that has been genetically altered to produce selected rapamycin analogs. Then, in collaboration with the Buck Institute for Research on Aging, we will test the binding specificities of these natural rapamycin analogs for mTOR1C and mTOR2C. If we find analogs with the desired properties, future experiments will be initiated using standard animal lifespan assays and other animal disease models through a collaboration with both the Buck Institute and Delos Pharmaceuticals for further drug development. Successful production and characterization of a range of natural rapamycin analogs will provide strong proof of concept that the Radiant Genomics natural product discovery platform will allow scientists to quickly interrogate the natural diversity surrounding a targeted natural product, an impossibility using traditional natural product discovery methods, and would revolutionize the field of natural product discovery.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R43
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    211500
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
  • Funding ICs
    NIA:211500\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    RADIANT GENOMICS, INC.
  • Organization Department
  • Organization DUNS
    078535589
  • Organization City
    BERKELEY
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    947102451
  • Organization District
    UNITED STATES