# Balancing Cellular Repair and Regeneration in Aging and Disease

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $127,710

## Abstract

PROJECT SUMMARY/ABSTRACT
Background: Aging is an incredibly plastic process that is dictated by coordinated repair and regenerative
mechanisms. Loss of this coordination marks the start of tissue decline and aging, thereby increasing disease
susceptibility. Alarmingly, age-dependent diseases are disproportionately rising in young age groups without
known cause. Early-Age Onset Colorectal Cancer (EAO CRC) is a prime example, which African Americans
experience the highest disease burden.
Rationale: Previously, we discovered a novel Hedgehog (Hh)-dependent mechanism that balances cellular
repair and regeneration to sustain healthy tissue aging. Specifically, we identified the Hh effector Patched (Ptc)
as a critical switch for balancing autophagy-based cellular repair and Hh-dependent regenerative proliferation.
Importantly, loss of Ptc function drives accelerated cellular aging. Hypothesis: We propose that the cells are
aging rapidly relative to chronological age, due to the loss of this Hh-dependent coordination of autophagy and
proliferation. We predict factors that promote aberrant Hh signaling predispose individuals to EAO CRC onset.
Specific Aims: To test this hypothesis, I will delineate the mechanism of Hh signaling in balancing autophagy
and proliferation to preserve cellular aging (Aim 1); define the Hh-dependent transcriptome during aging, with a
particular interest in identifying genes that are dysregulated in cancers impacting African Americans (Aim 2);
and functionally test the intersection of Hh signaling and genetic determinants of cancer disparities using both
the Drosophila intestines model and patient-derived colon organoids (Aim 3). This study will precisely define
fundamental mechanisms and aging-dependent cellular markers that are applicable to diseases impacting
African American communities. The culmination of this investigation will hone the required knowledge, technical
skillsets, and professional networks to successfully launch my independent research program, focused on
elucidating regulators of the autophagy-proliferation balance to reduce aging-related disease disparities.

## Key facts

- **NIH application ID:** 10865446
- **Project number:** 1K99AG086525-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jennifer Imena Alexander
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $127,710
- **Award type:** 1
- **Project period:** 2024-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865446

## Citation

> US National Institutes of Health, RePORTER application 10865446, Balancing Cellular Repair and Regeneration in Aging and Disease (1K99AG086525-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10865446. Licensed CC0.

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