# Comprehensive Resource for the Drosophila 4th chromosome

> **NIH NIH R24** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2022 · $311,746

## Abstract

The Alzheimer's related disease vascular dementia is due to an age-dependent accumulation of small blood
vessel ruptures in the brain. It affects almost a third of people over age 70. There is no treatment that reverses
the dementia that reflects the damage to the brain caused by broken vessels. A better understanding of the
molecular mechanisms underlying age associated cerebral blood vessel weakness is the most likely path to
improved diagnostics and dementia prevention. The goal of this supplement is develop fly strains expressing
variants of ApoE and mutations involved in the inherited blood vessel weakness Hereditary Hemorrhagic
Telangiectasia (HHT) that will be employed to test two hypotheses for the causes of Alzheimer's disease and
vascular dementia. The hypotheses are: 1) that germline mutations generating HHT are recapitulated over time
by somatic mutations leading to age associated brain blood vessel weakness and 2) that HHT mutations
synergyze with APOE4 to accelerate blood vessel ruptures. This supplement is within the scope of the parent
award since we are funded to create a resource for the Drosophila 4th chromosome. This resource includes
new fly strains with loss of function mutations for each gene on the 4th, new fly strains expressing each gene
on the 4th and new fly strains expressing the two closest human homologs for each 4th chromosome gene. In
this supplement we will create new fly strains expressing human genes with APOE4 and HHT mutations and
employ them in a pilot project. The connection between the parent and supplement is that 4 of the 5 genes in
the pilot are on the 4th chromosome. We have already created many of the necessary strains and thus expect
to complete the pilot in one year. First we will create loss of function mutations in 5 fly genes (Apolpp and four
genes with homologs implicated in HHT). These mutations are engineered to drive transgene expression in the
mutant gene's native expression pattern. To set a baseline, expression of the fly gene corresponding to the
mutant is employed to rescue the mutant phenotype. Rescue experiments will focus on defects in the fly blood
brain barrier to mimic an APOE4 mutant phenotype and as an analog to the human vasculature for HHT
mutations. We then humanize the mutant flies by overexpressing the cognate human homolog to evaluate the
degree of rescue. The hypothesis is then tested by expressing ApoE variants and human homologs with HHT
mutations individually and in combinations. Combinatorial experiments allow assessment of enhancing and
suppressing interactions. Phenotypic differences between males and females as well as age-dependent
increases in penetrance will be noted. The strains we generate can be employed to study other ApoE and HHT
related diseases in humanized flies by the community. Our results will likely stimulate efforts to replicate our
findings in vertebrate models of aging, dementia and Alzheimer's disease. Vertebrate model experiments could
provide th...

## Key facts

- **NIH application ID:** 10491507
- **Project number:** 3R24OD028242-03S1
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** STUART J NEWFELD
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $311,746
- **Award type:** 3
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491507

## Citation

> US National Institutes of Health, RePORTER application 10491507, Comprehensive Resource for the Drosophila 4th chromosome (3R24OD028242-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10491507. Licensed CC0.

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