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Principal Investigator: MAHADEVAN Raj RAJASEKARAN
Organization: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
Fiscal Year: 2024
Award: $215,250
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
ABSTRACT
Fecal incontinence (accidental leakage of stools; FI) is a major medical illness, occurs in a significant
population of women (>7%) and is under reported. Most common cause of FI is childbirth related injury to the
external anal sphincter (EAS), pelvic floor muscles and pudendal nerve (PN) that innervates sphincter muscle
by a variety of mechanisms. Many FI patients show anatomical disruptions and impairment of EAS muscle
function. Our animal (rabbit) studies confirm these findings and further demonstrate abnormal healing with
increased fibrosis in the regenerating muscle after experimental injury. Our mechanistic studies show
upregulation of fibrosis network involving Wnt-β/ STAT-3 proteins and a novel central hub for multi-receptor
driven profibrogenic signaling, Gα-interacting vesicle-associated protein (GIV; also known as Girdin) in the
injured animals. We hypothesize that PN stretch/crush during childbirth impairs sphincter function and
sustained neurotrophic (using brain derived neurotrophic factor; BDNF) therapy would accelerate PN re-
growth. Innovative, multimodular therapies that target nerve and muscle regrowth would prevent EAS muscle
dysfunction. Our specific aims are to: i. evaluate efficacy of a novel BDNF sustained release formulation
in a dual injury (PN crush and EAS injury) model alone and 2. In combination with GIV- siRNA delivered as
sustained release lipid nanoparticle formulation (LNP). We will use a female rabbit model and several
novel approaches, 1; longitudinal assessment of in-vivo length tension function of the EAS muscle, 2; use of
BDNF for sustained neurotrophin delivery, 3; gene silencing (GIV siRNA) with LNP to modulate fibrogenic
signaling with a goal of improving sphincter function in our studies. Thus, our proposal is both conceptually
novel, and innovative (paving the way for new treatment strategies). Rabbits will be monitored for 180 days
and subjected to EMG, anal canal pressure and sphincter muscle thickness (using endoluminal ultrasound)
measurements at pre-determined time points to determine anatomical and functional recovery. All the animals
will be sacrificed at the end of the study and EAS tissues will be harvested to perform tissue analysis to
determine nerve and muscle regeneration. Use of sustained BDNF therapy to promote EAS function remains
unexplored, as does the beneficial role of this multimodal approach. We have enlisted international leaders in
these fields for this novel research and our team has all the expertise to conduct this innovative study. Our
proposal aligns with R21 goals intended to support high risk, high payoff research. We envision a strong
potential for translation where patients could benefit from a simple, one-time office procedure during which the
PN/EAS is injected with the proposed neurotrophin /siRNA (LNP) formulations using a transperineal approach
to prevent post-partum FI.
Terms: <Acceleration><Accidents><Affect><Age><Anal><Anal Incontinence><Anal Sphincter><Anal canal><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Animals><Anus><BDNF><Body Tissues><Bowel incontinence><Brain-Derived Neurotrophic Factor><Cell Communication and Signaling><Cell Signaling><Childbirth><Circular layer of muscularis propria of anal canal><Combined Modality Therapy><Deposit><Deposition><Development><Domestic Rabbit><Dysfunction><Electromyography><Evaluation><External Anal Sphincter><External anal sphincter structure><Extravasation><FDA approved><Fecal Incontinence><Feces><Female><Fibrosis><Formulation><Functional disorder><G-Proteins><GDP Dissociation Factor><GDP Dissociation Stimulators><GDP Exchange Factors><GDP-GTP Exchange Protein><GDP-GTP Reversing Factors><GTP GDP exchange factor><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Inactivation><Gene Silencing><Generalized Growth><Genes><Goals><Growth><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Exchange Factors><Guanine Nucleotide Exchange Protein><Guanine Nucleotide Regulatory Proteins><Guanine Nucleotide Releasing Factors><Guanyl-Nucleotide Exchange Factor><Guanyl-Nucleotide Releasing Factor><Harvest><Healing abnormal><Healing delayed><Histologic><Histologically><Impaired healing><Impairment><In Vitro><Incidence><Incontinence><Injury><Internal Anal Sphincter><International><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intramuscular><Laboratories><Leakage><Length><Measurement><Mediating><Medical><Modeling><Molecular><Monitor><Morphology><Multimodal Therapy><Multimodal Treatment><Muscle><Muscle Tissue><Muscle function><Natural regeneration><Nerve><Nerve Crush><Nerve Regeneration><Neurites><Neuro-regeneration><Neuroregeneration><Non-Polyadenylated RNA><Oryctolagus cuniculus><Osmosis><Pathologic Constriction><Pathological Constriction><Pathway interactions><Patients><Pelvic Floor Disorders><Pelvic Floor Muscle><Peripheral Nervous System><Physiologic><Physiological><Physiopathology><Placebos><Population><Postpartum Period><Prevention><Procedures><Protein Inhibition><Proteins><Public Health><Pump><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Rabbits><Rabbits Mammals><Receptor Protein><Recovery><Recovery of Function><Regeneration><Reporting><Research><Rest><Ribonucleic Acid><Role><Sham Treatment><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Interfering RNA><Sphincter><Spillage><Stenosis><Stretching><Technology><Testing><Therapeutic><Thick><Thickness><Time><Tissue Growth><Tissues><Trauma><United States><Up-Regulation><Upregulation><Validation><Vesicle><WNT Signaling Pathway><WNT signaling><Woman><ages><antifibrotic agent><antifibrotic medication><antifibrotic therapy><antifibrotic treatment><aspirate><axon regeneration><axonal regeneration><biological signal transduction><child birth><clinical translation><clinically translatable><combination therapy><combined modality treatment><combined treatment><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><exchange factor><experience><functional improvement><functional outcomes><functional recovery><healing><high risk><improve function><improved><improved functional outcomes><in vivo><inhibit protein><inhibit proteins><injured><injuries><injury recovery><injury to the vasculature><innovate><innovation><innovative><interventional strategy><ionization><lipid based nanoparticle><lipid nanoparticle><mRNA vaccine><mRNA-based vaccine><mid life><mid-life><middle age><middle aged><midlife><model of animal><multi-component intervention><multi-faceted intervention><multi-modal intervention><multi-modal therapy><multi-modal treatment><multi-modality><multicomponent intervention><multifaceted intervention><multimodal intervention><multimodality><muscle regeneration><muscular><myogenesis><native protein drug><nerve injury><nervous system regeneration><neural><neural injury><neural regeneration><neuromuscular><neuroregenerative><neurotrophic factor><neurotrophin><neutrophin><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathophysiology><pathway><pharmaceutical protein><post-partum><pre-clinical><preclinical><pressure><prevent><preventing><protein drug agent><protein inhibitions><protein-based drug><receptor><recovery after injury><recovery following injury><recovery post injury><regenerate><regenerated nerve><rehab strategy><rehabilitation strategy><screening><screenings><sham therapy><short interfering RNA delivery><siRNA><siRNA delivery><small interfering RNA delivery><social role><sphincter ani muscle structure><stool><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic protein><therapeutic target><transcriptional silencing><translational opportunities><translational potential><ultrasound><validations><vascular injury>