06297-0798
TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE · PublishedFlow-down relationship
PublishedSubrecipient and prime recipient
Subrecipient
TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THESubrecipient UEI
GM1XX56LEP58DBA name
—Business type
Private University or College1RParent organization
TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THEUEI GM1XX56LEP58Prime recipient
LANKENAU INSTITUTE FOR MEDICAL RESEARCHPrime UEI
X7Y6RNVA4NR6FAIN
R01DE021104Prime award key
ASST_NON_R01DE021104_075Program and purpose
Assistance award context
Assistance Listing number
93.121Assistance Listing title
Oral Diseases and Disorders ResearchAssistance type
Project Grant (B)Base assistance type code
04Action date
Sep 27, 2024Base obligation date
Apr 15, 2011Subaward description
Dr. George Hajishengallis, D.D.S., Ph.D., Principal Investigator.Dr. Hajishengallis has a longstanding interest long-standing interest in immune regulation and tissue homeostasis in periodontal disease and how aging affects these functions. He will be responsible for the administration and coordination of research activities in this project to be performed in his laboratory, including the design, troubleshooting, and execution of experiments. He will moreover be responsible for the analysis, interpretation, and publication of generated data. He will have weekly meetings with Drs. Lim and Saha (below) for updates on research progress. Dr. Hajishengallis will also have frequent discussions (at least weekly via phone, or e-mail correspondence; or in person at monthly intervals) with Dr. Heber-Katz (contact PI) to monitor progress of the consortium project component.Prime project description
A new model of regenerative healing via inflammation-modulating biomaterials - Abstract The ability to regenerate tissue in mammals has remained elusive. While the use of stem cell populations in the context of bio-scaffolds has shown promise as a potential means of replacing lost, damaged, or diseased tissue, significant challenges remain. An alternative approach is to attempt to evoke a classical in situ regenerative response emulating that seen in lower species such as newts. While this trait was thought to be lost in evolution, our observation (Heber-Katz) that the MRL mouse and related strains have a significant spontaneous regenerative capability demonstrates that the trait is retained in mammals. Studies over the past almost 20 years have culminated in the identification of the HIF-1α (hypoxia inducible factor) pathway as the central actor regulating regeneration in mice. HIF-1α is significantly elevated during the early phases of wound healing in MRL mice and inhibiting HIF-1α with si-RNA blocks regeneration entirely. When we mimicked this HIF-1α response in otherwise non-regenerating Swiss Webster mice the regeneration trait was conferred with the faithful replacement of tissue architecture indistinguishable from normal tissue. This was achieved using the PHD inhibitor 1,4-DPCA in a novel biomaterial construct (Messersmith) leading to the stabilization of high levels of HIF-1α in vivo. In this current proposal, we provide preliminary results suggesting that impressive healing is also seen in a mouse model of periodontal disease, ligature-induced bacterial accumulation leading to an inflammatory host response with bone loss (Hajishengallis model). We show that bone recovers, the periodontal ligament (PDL) is restored, and an unusually robust stem cell response in the tooth pulp and in periodontal tissue is found. We will use advanced molecular design to produce a biomaterial capable of achieving single dose and local delivery vs. the current three-dose delivery system. In addition to yielding a novel soft and bone tissue regeneration therapy, we believe that this system provides an impressive landscape of phenomena that will yield important mechanistic information about in- situ regenerative responses in oral tissues. In Aim 1, we will create new biomaterials to yield extended drug release to provide a single-dose treatment with rapidly degradable gels; in Aim 2, we will examine the effect of drug preparations, both original and new, on bone and PDL loss and regrowth using microCT and molecular analysis; in Aim 3, we will further explore the metabolic response after modulating HIF levels; and in Aim 4, we will determine mechanistic factors involved in the inflammatory, overall immune, and stem cell responses. In conclusion, a successful in-situ drug-induced regenerative therapy would significantly advance the treatment of periodontal disease beyond current surgical procedures.Federal assistance hierarchy
Awarding and funding organizations
Awarding department
Department of Health and Human Services (HHS)075Awarding agency
National Institutes of Health7529Awarding office
NIH National Institute of Dental & Craniofacial Research75NP00Funding department
Department of Health and Human Services (HHS)075Funding agency
National Institutes of Health7529Funding office
NIH National Institute of Dental & Craniofacial Research75NP00Where the assisted activity occurs
Place of performance
Address
—City
PhiladelphiaState
PennsylvaniaZIP
191046205Country
United StatesCongressional district
03Registered or reported subrecipient address
Subrecipient location
Address
3451 WALNUT ST STE 440ACity
philadelphiaState
PennsylvaniaZIP
191046205Country
United StatesCongressional district
03SAM.gov reporting identity
Report metadata
Report ID
27143449Report UUID
c604d432-fcd1-11ef-ab59-07eca35f602bSubmitted
Jan 13, 2025Report updated
Jan 13, 2025Record loaded
Jan 13, 2025
