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Principal Investigator: Adam G Berger
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2021
Award: $51,036
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Non-healing ulcers are a common complication of diabetes, resulting in decreased quality of life, elevated rates
of amputation, increased risk of mortality, and high healthcare costs. Unfortunately, current treatments remain
outdated and inadequate. In diabetes, neuropathy and microvascular changes in dermal tissue lead to
dysregulated molecular cues, resulting in chronic inflammation and reduced angiogenesis that prevent wound
healing. Poor angiogenesis is particularly critical given the importance of vasculature in supplying oxygen,
nutrients, and systemic signaling molecules. Impairment of angiogenesis is in part driven by aberrant expression
of coding messenger RNAs (mRNAs) and non-coding microRNAs (miRNAs) at various time scales. Thus, one
promising approach to alter the course of diabetic ulcers is to directly target the expression of upregulated RNAs
in the non-healing state using nucleic acid RNA-targeting therapies; however, delivery challenges render nucleic
acid therapies clinically unfeasible. To address these delivery challenges, the Hammond Lab has developed and
demonstrated self-assembled electrostatic deposition of nucleic acids through the layer by layer (LbL) technique,
which leverages iterative adsorption of polyelectrolytes of alternating charge, to create conformal coatings on
wound bandages with tunable release kinetics. I propose to develop and investigate temporally controlled
release strategies to locally deliver RNA-targeting therapies that promote angiogenesis and healing of
diabetic ulcers. In Aim 1, I will formulate staged release RNA-targeting bandages to promote wound healing
since staged release of therapy for multiple targets will allow the bandages to address different phases of wound
healing. A proof-of-concept bandage will be developed to elute RNA-targeting therapy to stimulate angiogenesis
in both the inflammatory and proliferative wound healing phases, and it will be tested for efficacy in vitro and in
a murine in vivo diabetic ulcer model. In Aim 2, I will identify potential synergies of pro-angiogenic anti-miRs
(miRNA inhibitors), as inhibition of gene expression with anti-miRs enables regulation of many genes along
defined tissue-specific signaling pathways to enhance angiogenesis. Since it is also unknown how delivery timing
of these anti-miR combinations may impact efficacy, we will leverage controlled-release LbL bandages to
investigate this. Through this research, I will advance the delivery of nucleic acids with biomaterial systems and
the targeting of aberrantly expressed coding and non-coding RNAs to promote healing of diabetic wounds. This
work will lay the groundwork for expansion of this platform approach to other diseases of impaired tissue
regeneration where timing the delivery to the healing process is critical, such as venous ulcers, mesenteric
ischemia, and myocardial infarction.
Terms: <(TNF)-α><Address><Adsorption><Amputation><Angiogenic Proteins><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Assay><Bandage><Bed Sores><Bedsore><Bioassay><Biocompatible Materials><Biologic Assays><Biological><Biological Assay><Biomaterials><Body Tissues><Cachectin><Cancers><Cardiac infarction><Charge><Chronic><Clinical><Co(beta)-cyano-7''-(2-methyl)adeninylcobamide><Code><Coding System><Complications of Diabetes Mellitus><Cues><Deposit><Deposition><Dermal><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Diabetic wound><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drugs><Effectiveness><Electrostatics><Endothelial Cells><Engineering><Excipients><Functional RNA><Gene Expression><Genes><Healing abnormal><Healing delayed><Health Care Costs><Health Costs><Health Insurance for Aged and Disabled, Title 18><Health Insurance for Disabled Title 18><Healthcare Costs><Histology><Human><Immune Cell Activation><Impaired healing><Impaired tissue repair><Impaired wound healing><Impairment><In Vitro><Inflammation><Inflammatory><Investigation><Ischemia><Kinetics><Knowledge><Lead><Macrophage Activation><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medicare><Medication><Mesenteric><Mesentery><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Molecular Analysis><Molecular Weight><Monocyte-Derived TNF><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Natural regeneration><Neuropathy><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acids><Nutrient><O element><O2 element><Oxygen><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Peptidyl Prolyl Hydroxylase><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Polymers><Pressure Sore><Pressure Ulcer><Process><Procollagen Prolyl 4-Hydroxylase><Procollagen-Proline Dioxygenase><Proline Hydroxylase><Proline,2-Oxoglutarate 4-Dioxygenase><Prolyl 4-Hydroxylase><Prolyl Hydroxylase><Protocollagen Prolyl Hydroxylase><QOL><Quality of life><RNA><RNA Gene Products><Recurrence><Recurrent><Regeneration><Regulation><Research><Ribonucleic Acid><Short interfering RNA><Signal Pathway><Signaling Molecule><Small Interfering RNA><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Techniques><Therapeutic><Time><Tissues><Title 18><Transfection><Translating><Treatment Efficacy><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcer><Ulceration><Untranslated RNA><VEGF><VEGFs><Varicose Ulcer><Vascular Endothelial Growth Factors><Venous Ulcer><Work><Wound Repair><Wound models><abnormal tissue repair><angiogenesis><base><biological material><cardiac infarct><chronic skin wound><chronic ulcer><chronic wound><controlled release><coronary attack><coronary infarct><coronary infarction><cytokine><death risk><decubitus ulcer><delayed wound healing><diabetes><diabetes ulcer><diabetic skin wound><diabetic ulcer><diabetic wound healing><drug/agent><effective therapy><effective treatment><efficacy testing><factor A><gene function><healing><health insurance for disabled><heart attack><heart infarct><heart infarction><heavy metal Pb><heavy metal lead><immune activation><improved><in vitro Assay><in vivo><inhibitor><inhibitor/antagonist><insight><intervention efficacy><lipid nanoparticle><mRNA><malignancy><miRNA><miRNAs><mortality><mortality risk><neoplasm/cancer><neuropathic><non-healing ulcer><non-healing wounds><noncoding><nonhealing ulcer><nonhealing wounds><nuclease><nucleic acid delivery><overexpress><overexpression><pathway><perfusion imaging><persistent wounds><pressure injury><prevent><preventing><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><response><siRNA><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><tissue regeneration><tissue renewal><tissue specific regeneration><tissue wound><tool><uptake><wound><wound closure><wound environment><wound healing><wound healing models><wound resolution><wounding><wounds>